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At least 775 records · Page 43Linked to original sources
PubMed2006

Successful therapy must eradicate cancer stem cells.

Despite significant improvements in cancer therapy, tumor recurrence is frequent and can be due to a variety of mechanisms, including the evolution of resistance and tumor progression. Cancer stem cells have been postulated to maintain tumor growth similar to normal stem cells maintaining tissue homeostasis. Recently, the existence of these malignant stem cells has been proven for hematological as well as some solid tumors. Tumor stem cells are not targeted by standard therapy and might be responsible for treatment failure and tumor recurrence in many patients. We designed a simple mathematical model to demonstrate the importance of eliminating tumor stem cells. We explored different therapeutic scenarios to illustrate the properties required from novel therapeutic agents for successful tumor treatment. We show that successful therapy must eradicate tumor stem cells.

Animals↗
PubMed2026

Integrating Radiogenomics and CSF-Based Liquid Biopsy Sequencing for Precision Neuro-Oncology.

Glioblastoma and diffuse gliomas pose major therapeutic challenges due to marked intratumoral heterogeneity, limited tissue accessibility, and the blood-brain barrier. Tissue-based next-generation sequencing (NGS) remains essential for WHO CNS5 molecular classification, yet it is invasive and poorly suited to serial monitoring. Two complementary non- or minimally invasive approaches have advanced rapidly: radiogenomics, which correlates multiparametric MRI features with genomic alterations, and cerebrospinal fluid (CSF) liquid biopsy sequencing, which detects circulating tumor DNA with high tissue concordance. This review examines the independent progress and synergistic integration of radiogenomics and CSF-NGS. Imaging signatures can non-invasively predict key drivers (IDH1/2, EGFR, TERT, PTEN, TP53) and molecular subtypes, while CSF-ctDNA sequencing enables real-time assessment of clonal evolution, therapy resistance (including post-temozolomide hypermutation), and residual disease. We discuss technical considerations, performance metrics, multimodal artificial-intelligence fusion, and emerging clinical applications for diagnosis, prognosis, treatment selection, and longitudinal surveillance. Critical challenges, standardization, prospective validation, and workflow integration are highlighted. By combining the spatial phenotypic information of radiogenomics with the temporal genomic resolution of CSF sequencing, this multimodal strategy offers a promising path toward precision neuro-oncology and reduced reliance on repeated invasive sampling.

Humans↗
PubMed2002

[Streptococcus pneumoniae strains resistance to macrolide, lincosamide, streptogramin, oxazolidinone and ketolide].

Over the last two decades, antimicrobial resistance in Streptococcus pneumoniae has been detected at an increasing rate. There have been several reports of increasing rate of macrolide resistance among the penicillin-resistant S. pneumoniae strains. The rapid evolution of such resistance necessitated new antimicrobials, such as streptogramins, oxazolidinones and ketolides, against beta-lactam and macrolide resistant pneumococci. This study was undertaken to determine the prevalence of macrolide resistance in pneumococci isolated in a Turkish University hospital and also to determine the activity of these newly developed agents against pneumococci. For that purpose a total of 264 pneumococci, isolated from clinical specimens, were tested for susceptibility against penicillin, erythromycin, clarithromycin, clindamycin, quinupristin/dalfopristin, linezolid and telithromycin by agar dilution method. Penicillin resistance and intermediate penicillin resistance was found in 7.6% and 40% of isolates respectively, while resistance rates of the tested isolates against erythromycin, clarithromycin and clindamycin were as 15.9%, 13.6% and 13.6%, respectively. Resistance to macrolides and clindamycin was higher among the penicillin-resistant isolates. No resistance was detected against quinupristin/dalfopristin, linezolid and telithromycin, except for four strains which had minimal inhibitory concentration (MIC) values of intermediately susceptible category to quinupristin/dalfopristin. These data indicate the presence of an important percentage of macrolide resistant pneumococci in our hospital. It can also be concluded that streptogramins, oxazolidinones and ketolides may be used as good alternatives especially in case of infections due to macrolide resistant pneumococci.

Anti-Bacterial Agents↗
PubMed2004

Cancer gene suppression strategies: issues and potential.

Oncogenes are ideal targets for therapies which down-regulate gene expression. However, effective modalities for altering gene expression in vivo have thus far proven to be elusive. Whilst there has been recent success with small molecule inhibitors of oncoprotein function, evolution of resistance to these agents has been observed in the clinical setting, indicating the need for combinations of therapies for cancer treatment. Strategies for in vivo gene down-regulation still hold promise for the treatment of cancer. The technologies relevant to such therapeutic strategies are discussed in terms of molecular action, delivery and choice of target gene. Consideration is given to the pre-clinical and clinical efficacy these agents have demonstrated to date.

Animals↗
PubMedDate not supplied

Using baseline CD4 cell count and plasma HIV RNA to guide the initiation of highly active antiretroviral therapy.

Conflicting evidence regarding the impact of baseline plasma HIV RNA and CD4 cell count on survival after the initiation of highly active antiretroviral therapy (HAART) in HIV-infected patients has resulted in wide variability in the expert recommendations regarding when to start therapy. Early initiation of HAART may result in avoidable toxicities and premature evolution of resistance, whereas delaying HAART may increase the risk of opportunistic infections and/or preclude a worse virological and clinical response to therapy. While there is widespread consensus that HAART can be delayed to a CD4 cell count of 0.350 x 10(9) cells/L, the range between this threshold and 0.200 x 10(9) cells/L remains controversial. Greater uncertainty surrounds the role of baseline plasma HIV RNA, with some guidelines recommending initiating HAART when this level rises above 55,000 c/mL regardless of baseline CD4 cell count. The following review examines the evidence in support of delaying the initiation of HAART to a CD4 cell count of 0.200 x 10(9) cells/L regardless of plasma HIV RNA levels and outlines supporting data from a Canadian prospective cohort study of antiretroviral naive patients treated with HAART.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Ribosomal crystallography: peptide bond formation, chaperone assistance and antibiotics activity.

The peptidyl transferase center (PTC) is located in a protein free environment, thus confirming that the ribosome is a ribozyme. This arched void has dimensions suitable for accommodating the 3' ends of the A-and the P-site tRNAs, and is situated within a universal sizable symmetry-related region that connects all ribosomal functional centers involved in amino-acid polymerization. The linkage between the elaborate PTC architecture and the A-site tRNA position revealed that the A- to P-site passage of the tRNA 3' end is performed by a rotatory motion, which leads to stereochemistry suitable for peptide bond formation and for substrate mediated catalysis, thus suggesting that the PTC evolved by gene-fusion. Adjacent to the PTC is the entrance of the protein exit tunnel, shown to play active roles in sequence-specific gating of nascent chains and in responding to cellular signals. This tunnel also provides a site that may be exploited for local co-translational folding and seems to assist in nascent chain trafficking into the hydrophobic space formed by the first bacterial chaperone, the trigger factor. Many antibiotics target ribosomes. Although the ribosome is highly conserved, subtle sequence and/or conformational variations enable drug selectivity, thus facilitating clinical usage. Comparisons of high-resolution structures of complexes of antibiotics bound to ribosomes from eubacteria resembling pathogens, to an archaeon that shares properties with eukaryotes and to its mutant that allows antibiotics binding, demonstrated the unambiguous difference between mere binding and therapeutical effectiveness. The observed variability in antibiotics inhibitory modes, accompanied by the elucidation of the structural basis to antibiotics mechanism justifies expectations for structural based improved properties of existing compounds as well as for the development of novel drugs.

Animals↗
PubMedDate not supplied

[Pharmacological treatment resistant schizophrenia].

In the clinical practice, there are three different terms to designate schizophrenic patients who do not improve with antipsychotic medication: treatment-resistant, treatment-refractory and non-respondent patients. Treatment resistance is neither a synonym of chronicity nor of severity nor seriousness. Therefore, for a patient to be considered resistant, several points must be taken into account. These points are: a) whether the schizophrenia is primary or secondary; b) its nature; c) presence of previous substance abuse; d) treatment compliance and tolerance, and presence of minor neurological signs. The most widely accepted criteria to define pharmacological treatment resistance in schizophrenia were initially developed around 1988 by Kane. Nowadays, the BPRS and Independent Living Skills Survey (ILSS) are the scales used to assess the levels of lack or response or of treatment resistance. To attain a suitable therapeutic evolution in schizophrenics resistant to treatment in antipsychotic medication assays, the following guidelines must be considered: Identifying the symptoms clearly and using medication with a suitable dose and duration. Taking into account that treatment resistance can be mistaken for treatment intolerance, non-compliance to treatment, inappropriate social support or inappropriate psychosocial treatment. Using up all single therapeutic agents before applying multiple agents. Preventing extrapyramidal effects by means of an adequate choice of the primary treatment. Maintaining a positive therapeutic attitude.

Antipsychotic Agents↗
PubMedDate not supplied

Effects of progressively increased doses of theophylline and of S 9795 on hemodynamics, blood gases and lung mechanics in dogs.

We investigated the effects of progressively increased i.v. doses of theophylline and of the newly introduced methylxanthine derivative S 9795 on hemodynamics, blood gases and lung mechanics in 2 groups each of 8 pentobarbital sodium-anesthetized dogs. The maximum plasma levels that were attained were 56.6 +/- 3.4 micrograms/ml (mean +/- S.E.) for theophylline and 12 +/- 1.2 micrograms/ml for S 9795. Theophylline increased heart rate and cardiac output, decreased arterial PO2, increased O2 consumption and did not affect lung mechanics. S 9795 decreased heart rate, increased systemic arterial pressure, O2 consumption (slightly) and pulmonary capillary wedge pressure (the latter only at the highest dose) and decreased lung compliance without change in lung resistance. The evolutions of heart rate, O2 consumption and pulmonary capillary wedge pressure differed significantly after theophylline compared to S 9795. These results show that in dogs, theophylline acts as a positive chronotrope, while S 9795 either has no such effect or acts as a negative chronotrope at high doses. None of the 2 methylxanthines appears to reduce normal bronchomotor tone.

Animals↗
PubMed1988

Non lymphoblastic T cell lymphomas with prevalent skin involvement different from mycosis fungoides or Sézary's syndrome. A retrospective study of 6 cases in Europe.

A retrospective study of 23 cases of nonlymphoblastic T cell lymphomas with no features of either mycosis fungoides (MF) or Sézary syndrome (SS) was carried out. 6 patients exhibited cutaneous (or mucous) lesions and are presented herein. There was no detectable visceral or node involvement except in 1 patient. 3 cases were immunologically proven to be of peripheral T cell origin. Except T cell lymphomas in Japan and in the Caribbean area, the frequency of prevalent skin involvement is reportedly very low in non-MF/SS non lymphoblastic T cell lymphomas. However, it is likely that this frequency has been underestimated in Western countries. The histologic features of our cases run the heterogeneous spectrum of recently described node-based forms of peripheral T cell lymphomas: 'angioimmunoblastic lymphadenopathy with dysproteinemia'-like lymphoma, large T cell lymphoma, multilobulated cell lymphoma, T zone lymphoma. The histologic pattern of skin infiltration was different from that of MF/SS. One case was initially suggestive of a pseudolymphoma and had a prolonged evolution but the other patients suffered from rapid extracutaneous involvement and fatal evolution with resistance to treatment. Cutaneous plasmacytomas were seen in 1 case. Hence, certain cutaneous T cell lymphomas exhibit histologic, immunological and developmental features similar to those of node-based peripheral T cell lymphomas but different from those of MF/SS.

Aged↗
PubMed1979

Course of antibiotic sensitivities in Escherichia coli and Staphylococcus aureus from animals.

In order to establish the evolution of resistance against the common antibiotics from the beginning of their use up to the present time, the sensitivity of Escherichia coli isolated from the cecum of wild boars was determined. The MIC's of E. coli from these animals in a zoological garden was examined for comparison. The samples from the wild boars were collected in five forests in the Belgian Ardennes. The MIC's obtained (Table 1) are comparable to the mean values given in the early literature concerning strains of human origin (Table 7). E. coli from wild boars in a zoological garden has less sensitivity than from domesticated animals. However, the MIC's of staphylococci from fecal matter of the animals in captivity were not markedly enhanced except for streptomycin (Table 3). It was striking to find that staphylococci were absent in all the fecal samples from the wild boars living in their natural environment. The specific habitat of staphylococci is in man. Wild boars are the ancestors of domestic pigs. The MIC's of E. coli from the latter were determined for evaluation of altered resistance. All isolated strains were fairly resistant to the six substances tested (Table 2). Chloramphenicol was still the most active antibiotic. Staphylococci from some domestic animals (pigs, cattle, chicken) were sensitive to all the substances tested except the aminoglucosides and ampicillin (Table 3). E. coli from pigs bred on large farms in Spain (Toledo and Badajoz Provinces) were also highly resistant (Table 4) to five compounds and sensitive to cephalotin, polymyxin B, furoxone, and Carbadox. The samples obtained from family farms also contained unsensitive strains (Avila Province). These animals had never been given antibacterial feed additives as was confirmed by examination of feed samples (Table 6). Staphylococci when present in the Spanish samples can be considered to be antibiotic sensitive with the same exceptions as in the Belgian samples and also unsensitive to chloramphenicol. The use of antibiotics in animal feed was very common in Spain as was shown by feed analysis (Table 6). The risk of transferable resistance by plasmids between animal species must not be very high. In some cases where resistance formation could be mediated by R-factors, sensitive E. coli or staphylococci were isolated. Resistance was not generalized among animals from the same farm or in adjacent sties. No explanation for this discrepancy was found.

Animal Feed↗
PubMed1995

[Interaction between anti-infective agents and phagocytes].

Metchnikoff was one of the first to suggest the need for cooperation between phagocytes and therapeutic agents for the benefit of health. After the hopes raised by the discovery and the tremendous development of antimicrobials, there is now a creeping pessimism faced with the parallel evolution of resistance strategies in the microbial world. Interest has now turned to the use of immunomodulatory drugs, alone or combined with anti-infectious agents. Another tendency is based on the possibility that antimicrobials directly interfere with the host-microbe interplay. This review is aimed at summarizing our knowledge of the interactions between antimicrobial agents and the phagocyte, still a cornerstone in the natural defence system. Despite the problems inherent in the analysis and clinical relevance of effects observed in the test tube this developing area of research could provide new therapeutic solutions beyond the year 2000.

Anti-Infective Agents↗
PubMedDate not supplied

Cyclosporine A, an alternative to the oral lichen planus erosive treatment.

We present a double-blind study in two groups afflicted with oral lichen planus erythematous of long evolution and resistant to other treatments. We tested on it a treatment with Cyclosporine A (CyA) which had been successfully used before by many dermatologists. In the group A we used mouthwashes with a 5 ml Cyclosporine A solution to a 10% in olive oil of 0.4 degrees of acidity for five minutes, three times a day for eight weeks. In the control group we used acetonide of triamcinolone 01% in aqueous solution. Patients in group A improved considerably in their symptomatology in a 90% against a 60% in group B. In group A we could appreciate a disappearance of the symptomatology after two weeks of treatment in 60% of patients against 30% in group B. CyA can be an alternative to the conventional treatments in the acute period of lichen planus although it can not be considered as a first option drug because of the high cost of the treatment. For long term, results are not so good and we consider that extensive studies are necessary.

Acute Disease↗
PubMed1996

HIV viral dynamics.

BACKGROUND: Elucidation of the underlying rapid turnover of virus and HIV infected cells in vivo was perhaps the most informative and exciting discovery in HIV and AIDS research in the last few years. This observation, based on the rapid drop in virus load following antiviral drug therapy promises to change significantly the way we view important aspects of interaction of the virus and its host. As a result, the paradigm for HIV infection has shifted from considering the long period of clinical latency as one of viral inactivity, to viewing it as an active steady state of constant virus replication and cell death. This period should also be viewed as an integral part of the disease process, not simply a prolog to frank AIDS. METHODS: Here, I discuss the theoretical basis of the steady state model of HIV infection as well as its important consequences for understanding and controlling HIV pathogenesis. These include the significance of genetic variation and the establishment and evolution of the virus quasispecies, the evolution of resistance of the virus to antiviral therapy, and the theoretical and practical significance of virus load measurements. Emphasis is on discussion of recent developments as well as areas where our understanding still has significant gaps.

Antiviral Agents↗
PubMed1996

[Extra-hospital consumption of anti-infective agents in a defined daily doses per thousand inhabitants per day].

OBJECTIVES: To analyse the non-hospital use of drugs against infection (excluding antivirals and antimycotics) in the province of Zaragoza during 1994 by means of the application of the concept of the defined daily dose (DDD) as a technical unit of measurement, and defined daily dose per 1000 inhabitants per day (DID) as an indicator to facilitate comparison. DESIGN: A retrospective observational study. SETTING: Primary care. PARTICIPANTS: All the prescriptions for medicines to combat infection filled outside the hospital (940,662 units) in the province of Zaragoza. These following subgroups: J01 Systemic antibiotics, J03 Systemic chemotherapy drugs, J04A Tuberculosis, G04A Antiseptic and urinary infection drugs and R05C1 Mucolytic and anti-infection expectorants. MEASUREMENTS AND MAIN RESULTS: 8.6% of the total medicine prescribed in 1994 were drugs to combat infection, with 17.70 DID. The 4 most commonly prescribed subgroups were: penicillin, macrolides, tetracycline and cephalosporins. The 10 most commonly used active principals were, in descending order: amoxycillin, amoxycillin/clavulanic, erythromycin, cotrimoxazol, doxycyclin, cyprofloxacin, norfloxacin, roxythromycin, clarithromycin, pipemidic acid. CONCLUSIONS: The use of drugs to combat infection in our province is essentially no different from what other authors have observed. It would be interesting to carry out a follow-up study on the use of third-generation fluorquinolones and cephalosporins in primary care and to relate use of them to the evolution of resistance to anti-microbe drugs.

Anti-Bacterial Agents↗