Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations.

BRAFV600E melanoma patients, despite initially responding to the clinically prescribed anti-BRAFV600E therapy, often relapse, and their tumors develop drug resistance. While it is widely accepted that these tumors are originally driven by the BRAFV600E mutation, they often eventually diverge and become supported by various signaling networks. Therefore, patient-specific altered signaling signatures should be deciphered and treated individually. In this study, we design individualized melanoma combination treatments based on personalized network alterations. Using an information-theoretic approach, we compute high-resolution patient-specific altered signaling signatures. These altered signaling signatures each consist of several co-expressed subnetworks, which should all be targeted to optimally inhibit the entire altered signaling flux. Based on these data, we design smart, personalized drug combinations, often consisting of FDA-approved drugs. We validate our approach in vitro and in vivo showing that individualized drug combinations that are rationally based on patient-specific altered signaling signatures are more efficient than the clinically used anti-BRAFV600E or BRAFV600E/MEK targeted therapy. Furthermore, these drug combinations are highly selective, as a drug combination efficient for one BRAFV600E tumor is significantly less efficient for another, and vice versa. The approach presented herein can be broadly applicable to aid clinicians to rationally design patient-specific anti-melanoma drug combinations.

Sound velocities in olivine at Earth mantle pressures.

The independent elastic constants of an upper mantle mineral, San Carlos olivine [(Mg(1.8)Fe(0.2))SiO(4)], were measured from 0 to 12.5 gigapascals. Evidence is offered in support of the proposition that the explicit temperature dependence of the bulk modulus is small over the range of temperatures and pressures thought to prevail above the 400-kilometer discontinuity, and thus the data can be extrapolated to estimate the properties of olivine under mantle conditions at a depth of 400 kilometers. In the absence of high-temperature data at high pressures, estimates are made of the properties of olivine under mantle conditions to a depth of 400 kilometers. In contrast with low-pressure laboratory data, the predicted covariance of shear and compressional velocities as a function of temperature nearly matches the seismically estimated value for the lower mantle.

Physical influences on right ventricular infarction and cardiogenic shock in acute myocardial infarction.

AIM: To determine if complicated acute myocardial infarction (AMI) is related to specific cosmophysical activities. METHODS: The study group included 1170 patients who had undergone primary percutaneous coronary intervention (PCI) for AMI in 2000-2006. Geomagnetic and cosmic ray (neutron) activity (GMA, CRA) on the day of PCI were derived from international observatories. The findings were compared among patients with right ventricular infarction (RVI), cardiogenic shock, and uncomplicated AMI. RESULTS: Relative to the whole study period, the mean CRA was higher on days on which PCI was performed for RVI (n=123, 10.5%) (p = .0003) and cardiogenic shock (n=102, 8.72%) (p = .018). When the same artery was involved (LAD, RCA, CRX), CRA was significantly higher for complicated than for uncomplicated AMI (RVI group: p = .006, p = .00027, p = .014, c ardiogenic shock: p = .009, p = .029, p = .089, respectively). At the highest levels of GMA, more RVI cases were seen than cases of cardiogenic shock (p = .06). CONCLUSION: RVI and cardiogenic shock were associated with higher CRA than uncomplicated AMI. RVI occurred more often on days of high GMA than cardiogenic shock. Higher CRA may induce more myocardial damage in patients predisposed to AMI.

Influence of dietary fats on Ecstasy-induced hyperthermia.

BACKGROUND AND PURPOSE: Studies were designed to examine the effects of dietary fats on metabolic effects of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). These effects included hyperthermia, expression of uncoupling protein (UCP1 and 3) in brown adipose tissue or skeletal muscle and plasma free fatty acid (FFA) levels. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were fed either a high-fat diet (HFD, 60% kcal) or a lower fat isocaloric controlled diet (LFD, 10% kcal) for 28 days before MDMA challenge. KEY RESULTS: No significant differences were observed between LFD and HFD groups in terms of body weight, plasma thyroxine (T4) levels and expression of brown fat UCP1 or skeletal muscle UCP3 protein. HFD significantly raised levels of circulating FFA and potentiated the thermogenesis induced by MDMA (10 mg kg(-1), s.c.), compared to the effects of the LFD. Moreover, 30 and 60 min after MDMA administration, plasma FFA levels decreased in HFD animals, but were markedly elevated in the LFD group. CONCLUSIONS AND IMPLICATIONS: These results indicate that high-fat feeding regulates MDMA-induced thermogenesis by augmenting the activation of UCP rather than its expression.

Water-carbon dioxide solid phase equilibria at pressures above 4 GPa.

A solid phase in the mixed water-carbon dioxide system, previously identified as carbonic acid, was observed in the high-pressure diamond-anvil cell. The pressure-temperature paths of both its melting and peritectic curves were measured, beginning at 4.4 GPa and 165 °C (where it exists in a quadruple equilibrium, together with an aqueous fluid and the ices H2O(VII) and CO2(I)) and proceeding to higher pressures and temperatures. Single-crystal X-ray diffraction revealed a triclinic crystal with unit cell parameters (at 6.5 GPa and 20 °C) of a = 5.88 Å, b = 6.59 Å, c = 6.99 Å, α = 88.7°, ß = 79.7°, and γ = 67.7°. Raman spectra exhibit a major line at ~1080 cm-1 and lattice modes below 300 cm-1.

Risk Factors for Hospitalization of Home Hospice Enrollees Development and Validation of a Predictive Tool.

BACKGROUND: Over 10% of hospice patients experience at least 1 care transition 6 months prior to death. Transitions at the end of life, particularly from hospice to hospital, result in burdensome and fragmented care for patients and families. Little is known about factors that predict hospitalization in this population. OBJECTIVES: To develop and validate a model predictive of hospitalization after enrollment into home hospice using prehospice admission risk factors. DESIGN: Retrospective cohort study using Medicare fee-for-service claims. PARTICIPANTS: Patients enrolled into the Medicare hospice benefit were ≥18 years old in 2012. OUTCOME MEASURED: Hospitalization within 2 days from a hospice discharge. RESULTS: We developed a predictive model using 61 947 hospice enrollments, of which 3347 (5.4%) underwent a hospitalization. Seven variables were associated with hospitalization: age 18 to 55 years old (adjusted odds ratio [95% confidence interval]: 2.94 [2.41-3.59]), black race (2.13 [1.93-2.34]), east region (1.97 [1.73-2.24]), a noncancer diagnosis (1.32 [1.21-1.45]), 4 or more chronic conditions (8.11 [7.19-9.14]), 2 or more prior hospice enrollments (1.75 [1.35-2.26]), and enrollment in a not-for-profit hospice (2.01 [1.86-2.18]). A risk scoring tool ranging from 0 to 29 was developed, and a cutoff score of 18 identified hospitalized patients with a positive predictive value of 22%. CONCLUSIONS: Reasons for hospitalization among home hospice patients are complex. Patients who are younger, belong to a minority group, and have a greater number of chronic conditions are at increased odds of hospitalization. Our newly developed predictive tool identifies patients at risk for hospitalization and can serve as a benchmark for future model development.

Neutrons and sudden cardiac death (SCD) codes 121-125 ICD 10.

Recent studies have shown that (1) monthly neutron activity (NA) (imp/min) correlates with monthly number of acute myocardial infarction (AMI); (2) NA is higher on days of automatic implantable cardioverter defibrillators (AICD) discharges for VT, VF. Here we checked the level of NA in relation to timing and type of sudden cardiac death (SCD) patients [n=848 (579, 68.28% male)] obtained from the Kaunas registry for the years 2002-2004. All underwent Forensic Medicine post mortem examination and classification according to ICD10 by code 121-125. Daily NA data were obtained from Oulu U-ty, Finland and Moscow Monitoring Station of the Russian Academy of Sciences. No difference in NA was found on days with or without SCD. In men < 65, SCD occurred on days with higher NA than in women of the same age (p = 0.01) or in > 65 y old men (p = 0.045). Days of SCD with myocardial ruptures showed the highest level of NA, significantly higher than on all days (n = 669) of SCD (p = 0.037) and all 1096 days of the study (p = 0.0048). Three groups were accompanied by significantly higher NA: repeated AMI, myocardial ruptures (codes122, 123), and coronary atherothrombosis without AMI, related to electrical heart instability. The mechanism of possible neutron role in pathophysiology needs special studies.

Are neutrons involved in the pathogenesis of life-threatening cardiac arrhythmias?

Geomagnetic fields protect the earth from the adverse effects of cosmic rays, whose activity can be indirectly measured by monitoring the level of neutrons in the environment. The number and days of discharges from automatic implantable cardioverter defibrillators (ICD) in patients with cardiac arrhythmias are inversely correlated with the daily level of geomagnetic activity (GMA). The aim of the present was to determine whether neutron levels on days of AICD discharges are higher than average. Days on which discharges occurred were recorded in 31 patients bearing ICDs for managing ischemic cardiomyopathy. Daily neutron levels obtained from the monitoring data of the Russian Academy of Sciences in Moscow were analyzed using Student's t test. The mean (+/-SD) daily neutron level for the 1096-day period was 8299.29 +/- 294.236 imp/min (median 8252), and for days of ACID discharge, 8423.93 +/- 274.187 imp/min (median 8443) (p = 0.0002). The mean neutron activity on days of AICD discharges in response to ventricular disturbances was significantly higher than the mean level over the 1096-day study period. Whether this relation is a direct result of low GMA or due to an independent role of neutrons in the pathogenesis and timing of cardiac arrhythmias is unknown.

Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling.

The tumor microenvironment (TME) exerts critical pro-tumorigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility and invasion. Insulin-like growth factor-1 (IGF-1) and signal transducer and activator of transcription 3 (STAT3) stimulate colorectal cancer development and progression via cell autonomous and microenvironmental effects. Using a unique inhibitor, NT157, which targets both IGF-1 receptor (IGF-1R) and STAT3, we show that these pathways regulate many TME functions associated with sporadic colonic tumorigenesis in CPC-APC mice, in which cancer development is driven by loss of the Apc tumor suppressor gene. NT157 causes a substantial reduction in tumor burden by affecting cancer cells, cancer-associated fibroblasts (CAF) and myeloid cells. Decreased cancer cell proliferation and increased apoptosis were accompanied by inhibition of CAF activation and decreased inflammation. Furthermore, NT157 inhibited expression of pro-tumorigenic cytokines, chemokines and growth factors, including IL-6, IL-11 and IL-23 as well as CCL2, CCL5, CXCL7, CXCL5, ICAM1 and TGFß; decreased cancer cell migratory activity and reduced their proliferation in the liver. NT157 represents a new class of anti-cancer drugs that affect both the malignant cell and its supportive microenvironment.

Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling.

It is well known that specific signal transduction inhibitors rarely suffice as anti-cancer agents. In most cases, tumors possess primary drug resistance due to their inherent heterogeneity, or acquire drug resistance due to genomic instability and acquisition of mutations. Here we expand our previous study of the novel compound, NT157, and show that it acts as a dual-targeting agent that invokes the blockage of two signal transduction pathways that are central to the development and maintenance of multiple human cancers. We show that NT157 targets not only IGF1R-IRS1/2, as previously reported, but also the Stat3 signaling pathway and demonstrates remarkable anti-cancer characteristics in A375 human melanoma cells and in a metastatic melanoma model in mice.

Treatment of cancer-associated hypercalcemia with cisplatin.

Cisplatin (cis-platinum) has been shown to lower cancer-associated humoral hypercalcemia in an animal model and to inhibit bone resorption in vitro. This prospective study was designed to evaluate the efficacy of cisplatin in treating cancer-associated hypercalcemia in humans. Thirteen patients with severe hypercalcemia refractory to rehydration were treated with a 24-hour infusion of cisplatin, 100 mg/m2. Serial measurements of serum calcium and tumor size were made following cisplatin treatment and compared with pretreatment values. Nine patients (69%) achieved normocalcemia after treatment with cisplatin; and mean duration of benefit was 38 days in these patients. No reduction in tumor size was seen. All patients died of progressive cancer. We conclude that cisplatin can control malignant hypercalcemia for relatively long periods, and that its mechanism of action is not due to a reduction in tumor size.

Suicide-homicide temporal interrelationship, links with other fatalities, and environmental physical activity.

UNLABELLED: Homicide and suicide are extremes in human behavior. The aim of this study is to investigate the connection by time between suicide and homicide, between them and other fatalities, and their links with the level of cosmophysical activity. METHODS: Using the national database of Lithuania (1990-2002) we found that 547,875 deaths, 4,638 homicides (3,374 male) and 19,527 (16,019 male) suicides were registered in that period. Their temporal distribution over 156 months was compared with solar and cosmic-ray activity. Pearson correlation coefficients and their probabilities were established. RESULTS: There was a correlation between monthly rates of homicide and male groups. Female suicide rates correlated with male and total homicide numbers. Both homicide and suicide rates were inversely correlated with solar and cosmic-ray activity. Suicide numbers, but not homicides, were inversely related to geomagnetic activity. Suicide rates were inversely correlated with total, cardiovascular, traffic accident, and sudden deaths; homicide with total, traffic accident, and sudden deaths. CONCLUSION: Temporal distribution of homicide and suicide is significantly interrelated. Both are linked to parameters of cosmophysical activity. The influence of cosmic rays deserves special attention.

Effects of cisplatin on parathyroid hormone- and human lung tumor-induced bone resorption.

We have previously shown that dichlorodiamine platinum (DDP), or cisplatin, a cancer chemotherapeutic agent, is effective in the treatment of malignancy-associated hypercalcemia. In the present studies, we evaluated its effects on bovine parathyroid hormone (PTH)- or tumor-induced bone resorption in vitro in the neonatal mouse calvarial bone resorption assay. PTH alone or tumor extract (TE) of a human squamous cell lung cancer alone caused a significant increase in the bone resorption and in the number of osteoclasts in the calvaria. The addition of 3 and 10 micrograms/ml DDP inhibited the PTH- or TE-induced bone resorption. Lower doses of 1 and 2 micrograms/ml DDP, although not effective in inhibiting the PTH-induced bone resorption, were effective in lowering the TE-induced bone resorption. The number of osteoclasts was also reduced by DDP treatment. We therefore conclude that DDP is effective in the treatment of malignancy-associated hypercalcemia by virtue of its inhibitory effects on osteoclast numbers and on bone resorption.

Urinary growth hormone in man: evidence for multiple molecular forms.

Human GH (hGH) consists of several molecular forms. Monomeric forms present in pituitary extracts include the single chain, 22,000 mol wt form (22K; hGH-B); a 20,000 mol wt, single chain variant (20K); three proteolytically cleaved, two-chain forms (hGH-C, -D, and -E), acetylated, deaminated, and slow-migrating forms. It is not known which of these forms are secreted in vivo or whether peripheral organs contribute to the interconversion between some of these hGH forms. To answer these questions, we studied the molecular forms of hGH excreted in urine from normal volunteers and from an acromegalic patient, as urinary hGH presumably reflects integrated plasma hGH. hGH was extracted from urine by hollow fiber diafiltration and concentration, followed by immunoadsorbent chromatography. The extracted hGH was examined by polyacrylamide gel electrophoresis under native as well as denaturing and reducing conditions and by isoelectric focusing. The predominant form of hGH in both normal urine and urine from the acromegalic patient was 22K, with small quantities (approximately 10%) of 20K and an unidentified acidic form also present. Cleaved forms with enhanced bioactivity (hGH-D and -E) and big hGH forms were not detectable. We conclude that 1) the pattern of urinary hGH suggests that spontaneously secreted and circulating hGH is composed of at least three hGH forms, with 22K predominating; 2) the pattern of urinary hGH is similar to that of plasma hGH after L-dopa stimulation; 3) hGH excreted in acromegaly is indistinguishable from hGH excreted by normal subjects; 4) only a minute fraction (less than 0.01%) of the hGH secreted reaches the final urine; and 5) renal interconversion among hGH forms does not appear quantitatively important.

Insulin receptors in acute infection: a study of factors conferring insulin resistance.

Acute infections are accompanied by tissue insulin resistance, as manifested by worsening of metabolic control in diabetic patients and decreased glucose tolerance in non-diabetic subjects. To clarify the potential role of altered insulin receptor status in this phenomenon, we studied [125I]insulin binding to monocytes in 7 otherwise healthy subjects during acute bacterial and viral infections of moderate severity. The values were compared to those obtained after convalescence (five patients) and those of 24 normal subjects. Insulin binding during infection, at a time when insulin resistance was demonstrable, was indistinguishable from convalescent or normal values. Plasma glucose and insulin levels, the insulin to glucose ratio, as well as plasma GH, cortisol, and FFA were significantly elevated during infection, while plasma glucagon, epinephrine, and norepinephrine levels were normal. We conclude that insofar as monocyte receptors are representative of other tissues, insulin resistance in infection is mediated at the postreceptor level.

Medical malpractice: a nonadversarial suggestion.

BACKGROUND: The current legal system for prosecuting medical malpractice claims has bred widespread discontent. It has increased costs, jeopardized the delivery of necessary medical services, and corroded the physician-patient relationship with mistrust and poor morale. METHODS: Analysis of fairness of compensation awards and deterrence of substandard medical services under the current system. RESULTS: Compensation awards are inconsistent and unfairly contingent on irrational, adventitious factors. The current system does not seem to have had a significant effect on detering poor medical practice or on improving medical practice in general. CONCLUSIONS: An alternative to the current litigation-oriented medical malpractice system should be established and centered around a four-member Medical Malpractice Tribunal composed of a general physician, an expert physician in the specialty area of the claim, an attorney, and a lay person. This tribunal would be empowered to investigate malpractice claims by gathering evidence and taking testimony from parties, experts, and witnesses. The tribunal could employ a table of treatment-related injuries in making findings as to physician liability and victim compensation. Such a system, through predictability, would likely increase malpractice prevention while decreasing legal costs and also costs associated with defensive medicine. Deterrence could be served by giving the tribunal power to recommend sanctions against substandard providers to appropriate licensing and disciplinary bodies and by requiring those found guilty of malpractice to contribute subsidies to a compensation fund.

Presence of prostaglandin E in lung tumors from normocalcemic patients.

Prostaglandin E levels were determined in the tumor and normal lung tissue in 14 normocalcemic patients with lung cancer. All of the tested extracts from tumor and normal lung tissue revealed the presence of prostaglandin E; the levels were significantly higher in tumor tissue as compared with normal lung tissue. All of the tested tissue culture media from the tumors and all but one of those tested from normal lung revealed the presence of prostaglandin E; the levels were significantly higher in tumor tissue as compared with normal lung. There was no correlation between the level of prostaglandin E production and subsequent development of hypercalcemia or bone metastases or the duration of survival. The studies suggest that production of prostaglandin E by the tumors is a common phenomenon even in normocalcemic patients, and therefore its presence in the tumor tissue from a hypercalcemic patient may not necessarily implicate prostaglandin E in the pathogenesis of hypercalcemia in that patient.

Which cuff size is preferable for blood pressure monitoring in most hypertensive patients?

The accuracy of blood pressure (BP) measurements in obese hypertensives is still controversial. We investigated whether a large sized cuff could be appropriate for BP measurements in patients with different arm circumferences. Fifty hypertensive patients (23 males and 27 females, mean age 54 +/- 12 years, mean weight 75 +/- 12 kg) underwent BP measurements under standardised conditions using both a standard cuff (23 x 12 cm) and a large cuff (34 x 15 cm). Ambulatory blood pressure monitoring (ABPM) was subsequently performed in each subject using a large cuff. The average of two measurements performed in the clinic was compared with the mean daytime measurements. Thirty-one subjects had an arm circumference of < 30 cm (group 1) and weighted 68 +/- 10 kg, while 19 (group 2) had a larger arm circumference (> or = 30 cm) and were overweight (86 +/- 8 kg). BP in group 1 was 149 +/- 23/91 +/- 12 mmHg with the standard cuff and 143 +/- 24/88 +/- 13 mmHg with the large cuff (P < 0.003). In group 2, the respective readings were 153 +/- 22/100 +/- 16 mmHg (standard cuff) and 144 +/- 19/93 +/- 16 mmHg (large cuff; P < 0.0004). These findings suggest that in overweight hypertensives, the use of the standard cuff results in overestimation of BP and that large cuffs should be used exclusively in this population. The use of a large cuff in lean patients has yet to be clarified.

Distribution of monthly deaths, solar (SA) and geomagnetic (GMA) activity: their interrelationship in the last decade of the second millennium: the Lithuanian study 1990-1999.

Thirty percent of cardiovascular deaths cannot be explained by known risk factors. In this study, we sought links between 1) circannual rhythmicity, solar activity (SA) - sunspot number, solar radioflux and geomagnetic activity (GMA) - Ap., Cp., Am. with monthly number of deaths looking for environmental influence on mortality at the end of the second millennium. The Lithuanian national death data from for 120 consecutive months according to the IDC (1990 - 1999, n = 424925 deaths) was studied: 157189 from IHD (72144 male, 85045 female), 50228 from stroke (19062 male, 31166 female), 33722 from accidents (26193 male, 7529 female), 10655 from road accidents (8127 male, 2528 female) and 14810 from suicide (12137 male, 2673 female), 217508 - non cardiovascular (134308 male, 83200 female). Monthly death numbers (total, < 65y, 65-74, > 74y old for IHD and Stroke, and by gender) were compared with time of year, SA and GMA indices obtained from the National Geophysical Data and National Space Services Center, USA. Circannual rhythmicity indices, Pearson correlation coefficients and their probabilities were obtained and analyzed. The interrelationships of deaths from IHD and stroke and some other pathologies were also studied. In addition a multivariate linear regression analysis was done in order to evaluate the influence of time (month), Solar (S.A.) and Geomagnetic (GMA) activity on the temporal distribution of deaths. The total IHD monthly death number was significantly linked with GMA indices (r = 0.2-0.24, p = 0.03-0.075), but not with SA. IHD correlated with SA (r = 0.25-0.27, p = 0.006-0.0026), only in the 74 year age group. p = 0.0001) In the 65-74 age group, there was an inverse relationship with SA (r = -0.46-0.44) and no significant relationship to GMA. The IHD death number was correlated with GMA only in the < 65 and > 74 year age group (r = 0.30-0.36, p = 0.001-0.001). 2) Stroke-related deaths showed an inverse correlation with SA and GMA only for the 65-74y age group (r = -0.5, p = 0.0001 - SA, r = -0.4, p = 0.0001- GMA) and with GMA at age < 65 only for males (r = 0.20-0.25, p = 0.03-0.04). 3) Both IHD and stroke were strongly circannual rhythmic with acrophase at month 1.27 (IHD) and 1.32 (stroke) - first half of February, (p = 0.0001). 4) The IHD / stroke death ratio was correlated both with SA and GMA (r = 0.35, p 0.0001 - SA, r = 0.40-0.44, p = 0.0001 - GMA). 5) There was a strong inverse monthly deaths correlation between IHD and suicide (n = 14,810, r = -0.53, p = 0.0001). Stroke and suicide were also related, but to a much weaker extent (r = -0.217, p = 0.017). Accidents were inverse related to S.A. (r = -0.286, p = 0.0015), but not to GMA. Road Accidents - with both S.A. (r = 0.427, p < 0.0001) and GMA (r = 0.258, p = 0.004); with acrophases in October for road and November for other fatal accidents. Non cardiovascular deaths were annually rhythmic only for female - acrophase in early February, and for both gender inverse related to S.A. (r = -0.57, p < 0.0001) but not with GMA. Suicide victims had their acrophase in July (p < 0.0001) and were inverse related to S.A. (r = -0.6, p < 0.0001) and GMA (r = -0.27, p = 0.002). At the onset of the third millennium, the temporal distribution of deaths is still related to environmental physical activity. Those links differ for each of the pathologies, and by age and gender.

Childhood sexual experience and bulimia.

The relationship between childhood sexual experiences and bulimia was examined. Sixty-three females completed the Bulimia Test (BULIT) and the Sexual Events Questionnaire. BULIT scores were positively correlated with greater numbers of sexual experiences, experiences with adults and relatives, and negative responses of fear or shock at the time of the sexual experience. A multiple regression analysis indicated that fear/shock was a significant predictor of BULIT scores, accounting for 44% of the variance. Additional analyses indicated that bulimics reported a greater number of fear reactions following their sexual experiences and were less likely to have told anyone about their experiences.