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Biomedical subjects

K Hess

Publications and source records attributed to K Hess.

At least 19 recordsLinked to original sources
PubMed2006

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo.

Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC(50) values for WP1066 were 5.6 muM in U87-MG cells and 3.7 muM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X(L) and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (P<0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

Antineoplastic Agents↗
PubMed2006

CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease.

OBJECTIVES: To analyze the diagnostic sensitivity and specificity of various brain-derived proteins (14-3-3, Tau, neuron specific enolase [NSE], and S100b) in the CSF of patients with Creutzfeldt-Jakob disease (CJD) and to analyze biologic factors that modify these parameters. METHODS: CSF was tested for 14-3-3, Tau, NSE, and S100b in 1,859 patients with sporadic, genetic, iatrogenic, and variant CJD, and in 1,117 controls. RESULTS: The highest sensitivity was achieved for 14-3-3 and Tau in sporadic CJD (85% and 86%), and a combined determination of 14-3-3 and Tau, S100b, or NSE increased the sensitivity to over 93%. A multivariate analysis showed that the sensitivity of all tests was highest in patients with the shortest disease duration, age at onset >40 years, and homozygosity at codon 129 of the prion protein gene. In a group of patients with repeated lumbar punctures, a second test also increased the diagnostic sensitivity. CONCLUSIONS: The detection of elevated levels of brain-derived proteins in the CSF in patients with suspected Creutzfeldt-Jakob disease is a valuable diagnostic test. A second lumbar puncture may be of value in patients with atypical clinical course in whom the first test was negative.

14-3-3 Proteins↗
PubMed2006

Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy.

INTRODUCTION: Patients with end-stage liver disease often develop hepatic encephalopathy. The loss in cognitive abilities results in marked economic loss to the patient and health care community. We report hospital admission rates and economic impact of patients with end-stage liver disease suffering from hepatic encephalopathy. METHODS: The medical records were reviewed involving liver transplant patients started on lactulose or rifaximin therapy after presenting with stage 2 hepatic encephalopathy from January 2004 to November 2005. Information collected included demographics, hospitalizations required for hepatic encephalopathy, economic data, and Model for End-stage Liver Disease (MELD) score. RESULTS: Thirty-nine patients met study criteria: 24 patients treated with lactulose (group one) and 15 with rifaximin (group two). Group one included 18 men and six women of mean age 48 (range 39 to 58), average MELD 14 (range 10 to 19). Group two included 10 men and five women of mean age 47 (range 42 to 58), average MELD 15 (range 10 to 19). Group one patients required 19 hospitalizations overall: three patients with three hospitalizations, four patients with two hospitalizations, and two patients required one hospitalization. Total drug cost per month was 50 dollars(group one) and 620 dollars(group two). The average annual cost of hospitalization, emergency room visit, and drug per patient treated was 13,284.96 dollars for a total of 318,839 dollars (range 5005 dollars to 26,255 dollars, including drug cost and hospital care). Group two required three hospitalizations, all three with one visit. The average annual cost of hospitalization, emergency room visit, and drug per patient treated was 7958.13 dollars for a total of 119,372 dollars (range 6005 dollars to 19,255 dollars, including drug cost and hospital care). The total cost of therapy per patient per year was 13,285 dollars (group one) versus 7958 dollars (group two). The average length of stay was shorter in group two [3.5 days (range 3 to 4)] versus group 1 [5.0 days (range 3 to 10); P < .0001]. CONCLUSION: These pilot data demonstrate the marked difference in economic costs for the treatment of hepatic encephalopathy. The results also show that in comparative groups, the economic gains are quickly lost when using lactulose.

Adult↗
PubMed2005

Combination chemotherapy with 13-cis-retinoic acid and celecoxib in the treatment of glioblastoma multiforme.

In a phase II clinical trial, we sought to determine if combining celecoxib with 13-cis-retinoic acid (13-cRA, Accutane) was efficacious in the treatment of recurrent (progressive) glioblastoma multiforme (GBM). In parallel, we also sought to determine to what extent the outcomes from this clinical trial correlated with the findings from studies utilizing two murine intracerebral GBM models, U87MG and U251HF, to determine the predictive value of these murine models. In the clinical trial, 25 patients were studied at recurrence. Stable disease, which occurred in 44% of the patients, was the best response. The median progression-free survival (PFS) was 8 weeks, with a PFS at 6 months of only 19%. For the patients with stable disease, the median PFS was 24 weeks. The toxicity profile was unremarkable. The modest effect on PFS seen in this study agreed with the recent findings of another study, which showed a 19% PFS at 6 months in patients treated with 13-cRA alone. Thus, the combination of 13-cRA with celecoxib is not more effective than 13-cRA in the treatment of progressive GBM. In the murine model study, we found that long-term dosing with 13-cRA or celecoxib alone or in combination did not increase survival in animals with U87MG tumors but modestly increased survival in animals with U251HF tumors. There was no evidence of synergism between the two drugs. From this, we concluded that the animal studies generally predicted that the two agents would have only a modest effect alone and no additive effect when given in combination to patients.

Adult↗
PubMed2005

Effect of corticosteroids on short-term and long-term memory.

The effect of acute high-dose glucocorticoid therapy on memory function in patients with acute optic neuritis (n = 9) and multiple sclerosis (n = 21) was studied. All patients had reversible impairment of long-term memory functions, whereas measures of short-term memory, attentional functions, and alertness remained unaffected.

Adolescent↗
PubMed2005

MR-spectroscopic imaging during visual stimulation in subgroups of migraine with aura.

Migraine pathophysiology possibly involves deficient mitochondrial energy reserve and diminished cortical habituation. Using functional magnetic resonance spectroscopic imaging (fMRSI), we studied cortical lactate changes during prolonged visual stimulation to search for different pathophysiological mechanisms in clinically distinct subgroups of migraine with aura. Eleven healthy volunteers (HV) and 10 migraine patients were investigated interictally: five with visual aura (MA) and five with visual symptoms and at least one of the following: paraesthesia, paresis or dysphasia (MAplus). Using MRSI (Philips, 1.5 T) (1)H-spectra were repeatedly obtained from a 25 mm-thick slice covering visual and non-visual cortex, with the first and fifth measurements in darkness and the second to fourth with 8-Hz checkerboard stimulation. In MAplus lactate increased only during stimulation, only in visual cortex; in MA resting lactate was high in visual cortex, without further increase during stimulation. This is compatible with an abnormal metabolic strain during stimulation in MAplus, possibly due to dishabituation, and a predominant mitochondrial dysfunction in MA.

Adult↗
PubMed2004

Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer.

PURPOSE: The goal of this study was to examine the feasibility of developing a multigene predictor of pathologic complete response (pCR) to sequential weekly paclitaxel and fluorouracil + doxorubicin + cyclophosphamide (T/FAC) neoadjuvant chemotherapy regimen for breast cancer. PATIENTS AND METHODS: All patients underwent one-time pretreatment fine-needle aspiration to obtain RNA from the cancer for transcriptional profiling using cDNA arrays containing 30721 human sequence clones. Analysis was performed after profiling, and 42 patients' clinical results were available, 24 of which were used for predictive marker discovery; 18 patients' results were used as an independent validation set. RESULTS: Thirty-one percent of patients had pCR (six discovery and seven validation), defined as disappearance of all invasive cancer in the breast after completion of chemotherapy. We could identify no single marker that was sufficiently associated with pCR to be used as an individual predictor. A multigene model with 74 markers (P <or=.09) was built using data from the discovery samples and tested on the validation samples. Overall, a 78% (14 of 18) predictive accuracy was observed, with a 100% (three of three) positive predictive value for pCR, a 73% (11 of 15) negative predictive value, a sensitivity of 43% (three of seven), and a specificity of 100% (11 of 11). The expected response rate to T/FAC neoadjuvant therapy in unselected patients is 28%. CONCLUSION: Our results suggest that transcriptional profiling has the potential to identify a gene expression pattern in breast cancer that may lead to clinically useful predictors of pCR to T/FAC neoadjuvant therapy.

Adult↗
PubMed2004

Expression of sex hormone-binding globulin (SHBG) in human granulosa-lutein cells.

Sex hormone-binding globulin (SHBG) was classically thought to be a plasma steroid-carrying protein of hepatic origin, but recently, locally produced, membrane-bound SHBG has been shown to influence cell functions in several steroid-responsive tissues. In the ovary, SHBG is known to be present in the follicular fluid, but information about a possible intracellular presence of SHBG in this organ is still very scarce. In this study the presence of SHBG was assessed by immunohistochemistry in human granulosa-lutein cells (GLC) collected by follicle puncture for in vitro fertilization. SHBG was detected in the cytoplasm of GLC before and after in vitro culture for up to 96 h. The presence of full-length SHBG messenger RNA was demonstrated in GLC by reverse transcription-polymerase chain reaction (RT-PCR) in both cultured and uncultured cells. These results demonstrate a local synthesis of SHBG in GLC and raise the question of the physiological significance of these findings in follicular physiology.

Alternative Splicing↗
PubMed2004

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Clinical Trials as Topic↗
PubMed2003

Three-dimensional vestibular eye and head reflexes of the chameleon: characteristics of gain and phase and effects of eye position on orientation of ocular rotation axes during stimulation in yaw direction.

We investigated gaze-stabilizing reflexes in the chameleon using the three-dimensional search-coil technique. Animals were rotated sinusoidally around an earth-vertical axis under head-fixed and head-free conditions, in the dark and in the light. Gain, phase and the influence of eye position on vestibulo-ocular reflex rotation axes were studied. During head-restrained stimulation in the dark, vestibulo-ocular reflex gaze gains were low (0.1-0.3) and phase lead decreased with increasing frequencies (from 100 degrees at 0.04 Hz to < 30 degrees at 1 Hz). Gaze gains were larger during stimulation in the light (0.1-0.8) with a smaller phase lead (< 30 degrees) and were close to unity during the head-free conditions (around 0.6 in the dark, around 0.8 in the light) with small phase leads. These results confirm earlier findings that chameleons have a low vestibulo-ocular reflex gain during head-fixed conditions and stimulation in the dark and higher gains during head-free stimulation in the light. Vestibulo-ocular reflex eye rotation axes were roughly aligned with the head's rotation axis and did not systematically tilt when the animals were looking eccentrically, up- or downward (as predicted by Listing's Law). Therefore, vestibulo-ocular reflex responses in the chameleon follow a strategy, which optimally stabilizes the entire retinal images, a result previously found in non-human primates.

Adaptation, Physiological↗
PubMed2002

Action of boron at the molecular level: effects on transcription and translation in an acellular system.

It has been shown that boric acid has well-defined biological effects such as stimulation of wound healing in vivo, release of growth factors and cytokines, and increase of the extracellular matrice turnover. We examined its action at the molecular level, using cell-free systems of transcription (isolated placenta nuclei) and translation (wheat germ extract). We found that 10 mM boric acid greatly increased RNA synthesis, measured by absorbance at 260 nm (x 6.4) or by [3H]-UTP uptake (x 11). Full-length functional mRNA was produced because proteins of 14-80 kDa were translated. Among these proteins, factors involved in angiogenesis and, subsequently, in wound healing (VEGF and TGFbeta) were identified by slot blot, whereas growth factors such as FGF1 and TNFalpha were not detected. These results demonstrate that boron may contribute to biological cell activities at both the transcription and translation levels. However, the mechanism of action is still not known.

Autoradiography↗
PubMed2001

A possible loophole in the theorem of Bell.

The celebrated inequalities of Bell are based on the assumption that local hidden parameters exist. When combined with conflicting experimental results, these inequalities appear to prove that local hidden parameters cannot exist. This contradiction suggests to many that only instantaneous action at a distance can explain the Einstein, Podolsky, and Rosen type of experiments. We show that, in addition to the assumption that hidden parameters exist, Bell tacitly makes a variety of other assumptions that contribute to his being able to obtain the desired contradiction. For instance, Bell assumes that the hidden parameters do not depend on time and are governed by a single probability measure independent of the analyzer settings. We argue that the exclusion of time has neither a physical nor a mathematical basis but is based on Bell's translation of the concept of Einstein locality into the language of probability theory. Our additional set of local hidden variables includes time-like correlated parameters and a generalized probability density. We prove that our extended space of local hidden variables does not permit Bell-type proofs to go forward.

Journal Article↗
PubMed2001

Bell's theorem and the problem of decidability between the views of Einstein and Bohr.

Einstein, Podolsky, and Rosen (EPR) have designed a gedanken experiment that suggested a theory that was more complete than quantum mechanics. The EPR design was later realized in various forms, with experimental results close to the quantum mechanical prediction. The experimental results by themselves have no bearing on the EPR claim that quantum mechanics must be incomplete nor on the existence of hidden parameters. However, the well known inequalities of Bell are based on the assumption that local hidden parameters exist and, when combined with conflicting experimental results, do appear to prove that local hidden parameters cannot exist. This fact leaves only instantaneous actions at a distance (called "spooky" by Einstein) to explain the experiments. The Bell inequalities are based on a mathematical model of the EPR experiments. They have no experimental confirmation, because they contradict the results of all EPR experiments. In addition to the assumption that hidden parameters exist, Bell tacitly makes a variety of other assumptions; for instance, he assumes that the hidden parameters are governed by a single probability measure independent of the analyzer settings. We argue that the mathematical model of Bell excludes a large set of local hidden variables and a large variety of probability densities. Our set of local hidden variables includes time-like correlated parameters and a generalized probability density. We prove that our extended space of local hidden variables does permit derivation of the quantum result and is consistent with all known experiments.

Journal Article↗