Genetic Heterogeneity of MET-Aberrant NSCLC and Its Impact on the Outcome of Immunotherapy.

Introduction: Robust data on the outcome of MET-aberrant NSCLC with nontargeted therapies are limited, especially in consideration of the heterogeneity of MET-amplified tumors (METamp).

Methods: A total of 337 tumor specimens of patients with MET-altered Union for International Cancer Control stage IIIB/IV NSCLC were analyzed using next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry. The evaluation focused on the type of MET aberration, co-occurring mutations, programmed death-ligand 1 expression, and overall survival (OS).

Mimicking Tyrosine Phosphorylation in Human Cytochrome c by the Evolved tRNA Synthetase Technique.

Phosphorylation of tyrosine 48 of cytochrome c is related to a wide range of human diseases due to the pleiotropic role of the heme-protein in cell life and death. However, the structural conformation and physicochemical properties of phosphorylated cytochrome c are difficult to study as its yield from cell extracts is very low and its kinase remains unknown. Herein, we report a high-yielding synthesis of a close mimic of phosphorylated cytochrome c, developed by optimization of the synthesis of the non-canonical amino acid p-carboxymethyl-L-phenylalanine (pCMF) and its efficient site-specific incorporation at position 48.

Disentangling electron tunneling and protein dynamics of cytochrome c through a rationally designed surface mutation.

Nonexponential distance dependence of the apparent electron-transfer (ET) rate has been reported for a variety of redox proteins immobilized on biocompatible electrodes, thus posing a physicochemical challenge of possible physiological relevance. We have recently proposed that this behavior may arise not only from the structural and dynamical complexity of the redox proteins but also from their interplay with strong electric fields present in the experimental setups and in vivo (J. Am Chem.

Complex formation with the activator RACo affects the corrinoid structure of CoFeSP.

Activation of the corrinoid [Fe-S] protein (CoFeSP), involved in reductive CO(2) conversion, requires the reduction of the Co(II) center by the [Fe-S] protein RACo, which according to the reduction potentials of the two proteins would correspond to an uphill electron transfer. In our resonance Raman spectroscopic work, we demonstrate that, as a conformational gate for the corrinoid reduction, complex formation of Co(II)FeSP and RACo specifically alters the structure of the corrinoid cofactor by modifying the interactions of the Co(II) center with the axial ligand. On the basis of various deletion mutants, the potential interaction domains on the partner proteins can be predicted.

[Closure of bronchial fistulas using amplatzer vascular plugs].

Bronchial fistulas occurring either spontaneously in the course of malignant diseases of the chest or following pulmonary resections (lobectomy, pneumonectomy) are rare, but feared complications associated with high morbidity and mortality. In many cases a surgical approach to fistula closure is not possible. Numerous endoscopic procedures for fistula closure have been reported, mostly in the form of isolated case reports with until now no satisfying results.

Thermal fluctuations determine the electron-transfer rates of cytochrome c in electrostatic and covalent complexes.

The heterogeneous electron-transfer (ET) reaction of cytochrome c (Cyt-c) electrostatically or covalently immobilized on electrodes coated with self-assembled monolayers (SAMs) of omega-functionalized alkanethiols is analyzed by surface-enhanced resonance Raman (SERR) spectroscopy and molecular dynamics (MD) simulations. Electrostatically bound Cyt-c on pure carboxyl-terminated and mixed carboxyl/hydroxyl-terminated SAMs reveals the same distance dependence of the rate constants, that is, electron tunneling at long distances and a regime controlled by the protein orientational distribution and dynamics that leads to a nearly distance-independent rate constant at short distances. Qualitatively, the same behavior is found for covalently bound Cyt-c, although the apparent ET rates in the plateau region are lower since protein mobility is restricted due to formation of amide bonds between the protein and the SAM.

[Metastases from a malignant melanoma as extensive, space-occupying lesion in the trachea].

We report the case of a 71-year-old man, who was transferred to our clinic with rapidly increasing dyspnea. On examination by flexible bronchoscopy the trachea was found to be almost completely obstructed by metastatic masses of a malignant melanoma. After endoscopic removal of the obstruction, we inserted a covered nitinol stent which led to instantaneous relief of symptoms.

Survival, and time to an advanced disease state or progression, of untreated patients with moderately severe multiple sclerosis in a multicenter observational database: relevance for design of a clinical trial for high dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation.

Despite prolonged survival, patients with multiple sclerosis (MS) experience considerable morbidity, which adversely impacts quality of life. To assess the risk-benefit of a clinical trial of high dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation for MS, we sought to determine the natural history of the disease in a comparison group of untreated patients. We identified 285 individuals with 2132 combined observation years (median: 5.

[Prevalence, detection and prescribing behavior in depressive syndromes. A German federal family physician study].

This study examines the prevalence of depressive syndromes among unselected primary care patients as well as doctors' recognition and treatment rates. This nationwide study included a total of 20,421 patients attending their primary care doctors (n = 633) on the study's target day. Patients received a self-report questionnaire including the depression screening questionnaire (DSQ) to provide diagnoses of depressive disorders according to the criteria of DSM-IV and ICD-10.

Prevalence and recognition of depressive syndromes in German primary care settings: poorly recognized and treated?

The study examines the prevalence of depressive syndromes among unselected primary care attenders, as well as doctors' recognition and treatment rates, in order to examine patient and doctor-related factors associated with poor recognition. This nationwide study included a total of 20421 patients (aged 15-99 years) attending their primary care doctors (n = 633) on the study's target day in April 1999. Patients received a self-report questionnaire, including the Depression Screening Questionnaire (DSQ), to provide diagnoses of depressive disorders according to the criteria of DSM-IV and ICD-10.

Biomesogenic matrix systems.

The bifunctionally reactive nucleoside and distant nucleoside analogs adenosine (Ado), S-[(adenine-9-yl)methoxyethyl]-L-cysteine (Na-salt) (cysA) and 9-vinyladenine (vA) in aqueous solutions assemble on complementary polyuridylic acid templates to form complex lyomesophases. The systems are investigated by polarizing microscopy, differential scanning calorimetry (DSC) and 1H- and 31P-nmr spectroscopies, assisted by molecular modeling studies. The results indicate the importance of biomesogenic (pre)ordering in nucleic acid native and artificial matrix reactions.

A structure-function study of nucleic acid-fluorenone complexes.

Several 2.7-bis-[(dialkylamino)-acetylamino]-fluoren-9-one derivatives (fluoramides) were synthesized as analogues of the DNA binding compound tilorone (2,7-bis[(diethylamino)-ethoxy]-fluoren-9-one). Previous studies showed the drugs to induce cytokines and inhibit reverse transcription.

Self-assembly and lyomesophases formed by long-chain alkoxymethyl-nucleobase derivatives.

Amphiphilic complementary nucleobase derivatives, containing n-octadecyloxymethyl substituents at the N1 position of pyrimidine and N9 of purine, dissolved in chloroform form non-specific lyotropic mesophases, which were analyzed by optical polarizing microscopy. Molecular modeling studies visualize hypothetical horizontal and vertical nucleobase hydrogen-bonding and stacking arrangements, as well as aliphatic long-chain interstrand interaction.

[Amoxicillin/clavulanic acid in therapy of bacterial infections of the diabetic foot. Results of an observational study].

The results of an observational study of amoxicillin/clavulanic acid (Augmentan) in 191 patients are presented. The average duration of treatment was 15 days (median). Healing or improvement was observed in 76% of the cases.

A spectroscopic and thermodynamic study of Taxol nucleic acid complexes.

The interactions of natural and synthetic polynucleotide double strands with the antitumor agent paclitaxel and the oncological product "Taxol for Injection Concentrate" (abbreviated as taxol) were examined in diluted aqueous solutions by thermal denaturation profiles (Tm), CD spectra and UV-absorption measurements. Furthermore, DNA-paclitaxel and -taxol complexes in condensed nucleic acid solutions were studied by differential scanning calorimetry. As polynucleotides alternating and homologous poly[d(AT)] and poly[d(GC)] and calf thymus DNA were used.

Stabilization of Double Stranded Homologous Poly(dA)·Poly(dT) by Taxol.

Abstract The nucleic acid activity of taxol and paclitaxel was investigated with synthetic and natural oligo- and polynucleotides. The polynucleotides poly(dA)·poly(dT), poly(dG)·poly(dC), poly [d(A-T)]·poly[d(A-T)], poly[d(G-C)]·poly[d(G-C)] and calf thymus DNA were used. The oligonucleotides are 24-mers with d(purine)(24)·d(pyrimidine)(24) strands, as well as d[(purine)(x)-(pyrimidine)(x)]·d[(purine)(x)-(pyrimidine)(x)] sequences.

Demography, symptomatology, and course of disease in ambulatory zoster patients. A physician-based survey in Germany.

This survey summarises the observations of physicians who prospectively recorded clinically relevant data on their patients with an episode of herpes zoster. These included demography of patients, signs and symptoms during the prodromal phase, relevant history, description of disease at the first visit, therapeutic measures and description of disease, and occurrence of postherpetic neuralgia (pain 4-5 weeks after crusting) at the second visit. A total of 2,063 patients were reported to the data management centre.

Paroxetine and amitriptyline augmentation of lithium in the treatment of major depression: a double-blind study.

To study the efficacy and safety of antidepressant augmentation of ongoing lithium therapy, lithium-maintained patients suffering from an breakthrough episode of major depression were randomly assigned under double-blind conditions to receive paroxetine 20 mg/day (N = 19) or amitriptyline 75 mg/day (N = 23). The initial dosages could be increased after 2 weeks to 40 mg/day and 150 mg/day, respectively, and the patients were treated for a total of 6 weeks. Efficacy was assessed weekly with the 21-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impression Scale (CGI), and safety was assessed with the Dosage Record and Treatment Emergent Symptom Scale.

Characterization of antigens from the human exocrine pancreatic tissue (Pag) relevant as target antigens for autoantibodies in Crohn's disease.

Background: The present study was performed to analyse the immunological properties of the autoantigens recognized by autoantibodies against exocrine pancreas (PAb), which have been described in Crohn's disease.

Methods: Autoantibodies were detected by indirect immunofluorescence. Inhibition studies were performed by preincubating tissue sections with various glycoproteins and the different fractions obtained in fractioned salt precipitation of pancreas homogenate with ammonium sulphate.

A prognostic score for postherpetic neuralgia in ambulatory patients.

The main objective was to develop a scoring system for easy use by the physician in daily clinical practice in deciding the appropriate treatment for his herpes zoster patient. Data from 635 patients who did not receive antiviral therapy were included in this analysis. Of these, 131 developed postherpetic neuralgia (PHN).

DNA-drug interaction measurements using surface plasmon resonance.

The interactions of the drugs 2,7-bis[(diethylamino)-ethoxy]-fluoren-9-one dihydrochloride (Tilorone), 2,7-bis[(dipropylamino)-acetamido]-fluoren-9-one dihydrochloride (FA-2), 2'-(4-hydroxyphenyl)-5-(4-methyl-1-piperazinyl)-2,5'-bi-1H-benzimidazole trihydrochloride (Hoechst 33258), and hematoporphyrin IX derivative (HPD) with synthetic self-complementary DNA (36-b.p.; 5'-biotin-spacer-[d(CGCTATATAGCG)]3-3') were studied by SPR (Surface Plasmon Resonance).

The influence of strongly acidic groups on the protonation of peptides in electrospray MS.

In order to obtain experimental data on the question of compensation of positive charges by anionic groups in multiply charged ions of polyfunctional molecules in electrospray MS, several pairs of peptides with the same basic structure but differentiated by one or two strongly acidic groups (phosphate or sulfonate) were investigated. It was found that depending on the density of basic centers and the strength of acidic groups present, the observed changes upon introduction of acidic groups ranged from complete elimination of the most highly charged state to absence of any difference.