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At least 163 records · Page 9Linked to original sources

PubMed2026

Decoding context-dependent sirtuin pharmacology in cancer: Metabolic-epigenetic switches and precision therapeutic targeting.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Humans↗

PubMed1998

Wound healing. New modalities for a new millennium.

Common to all studies of wound healing modalities is the need to convert the chronic wound into an acute wound and to maintain the wound in an acute state while subsequently using adjunctive therapy. Hence, precise control and documentation of wound care is extremely important in order to avoid contamination of the effects of a specific modality with the effects of good wound care. Falanga has noted that neuropathy of diabetes has been given wide support as the primary pathogenic component of diabetic ulcers, whereas less recognition has been made of the wound-healing failure component. The therapies discussed in this article considered the wound-healing failure component. Oxygen is a drug. The use of oxygen under normobaric conditions at higher than normal inspired partial pressures is standard operating procedure when clinicians are faced with patients with respiratory embarrassment or heart failure. The use of oxygen under hyperbaric conditions, however, remains estranged from the mainstream thoughts of most clinicians. Abnormally hypoxic wounds may benefit from specific oxygen therapy in hyperbaric dosage ranges. However, correction of abnormal wound oxygen tension alone does not guarantee healing. Hyperbaric studies have been criticized for the lack of well-defined wound care protocols, the absence of precise wound healing measures, and poorly defined wound healing endpoints. Studies with growth factors and human skin equivalents exclude patients typically referred for hyperbaric therapy. Patients referred for hyperbaric therapy often have larger wounds with greater severity of peripheral vascular disease with ABIs < 0.7 and TcPO2 < 30 to 40 mm Hg, are often on medications known to inhibit wound healing (e.g., steroids), or have concomitant medical disorders (collagen vascular disease, renal failure) associated with poor healing. No hyperbaric study has controlled stringently for all of these factors. Nevertheless, HBO2 is more specific and successful for the intended purpose of correction of abnormal tissue oxygen tensions than are growth factors for the intended purpose of growth. Similarly, skin substitutes are limited in their application and have not been tried in patients with ABIs < 0.7 or TcPO2 values < 30 mm Hg. In our view, hyperbaric therapy probably can be combined successfully with allogenic grafts and human skin equivalents in this group of patients. Hyperbaric therapy can generate a sufficient granulation base in which these products should be able to close properly selected wounds successfully. No studies of this combined modality approach exist. Finally, regardless of the modality used to aid in wound closure, long-term outcomes probably depend more on neuropathy and large vessel disease than on microangiopathy and local wound-healing defects. The modalities presented in this article must prove to be both cost effective and practical before they are widely disseminated. Nevertheless, the ability to manipulate the local wound environment is no longer inviolate as was once presumed, and current investigations continue to advance therapeutic options in this most fascinating and challenging discipline.

Diabetic Foot↗

PubMed2026

From the Microscope to the Genome: A New Era in the Molecular Genetics of Epidermolysis Bullosa.

Epidermolysis bullosa (EB) is a heterogeneous group of inherited disorders characterised by skin fragility, caused by pathogenic variants in genes encoding structural components of the dermo-epidermal junction. With the advent of next-generation sequencing (NGS), the diagnostic paradigm has shifted from a morphological to a genotype-oriented approach. This review summarises the genetic architecture of EB, the types of mutations and genotype-phenotype relationships, the challenges in interpreting variants of unknown significance (VUS), and therapeutic strategies targeting specific mutational mechanisms, including read-through approaches, exon skipping and genome editing. The role of modifier genes and epigenetic factors in clinical variability is also discussed. The focus is on the translational potential of genomics for personalized therapy in EB. Overall, this review synthesizes the molecular basis of all four major EB types across 16+ classical genes, highlights the paradigm shift where NGS achieves a diagnostic yield exceeding 90%, and critically assesses recent therapeutic milestones-ranging from the first FDA-approved topical gene therapy to precision RNA and genome-editing modalities.

Humans↗

PubMed2004

Oxidative stress in cardiovascular disease: molecular basis of its deleterious effects, its detection, and therapeutic considerations.

PURPOSE OF REVIEW: The adoption of immediate reperfusion strategies to treat acutely occluded coronary arteries and the emergence of high-resolution molecular biology techniques have drawn attention to oxidative stress and reactive oxygen species generation in the cardiovascular system. Recent evidence suggests that oxidative stress is a common denominator in many aspects of cardiovascular pathogenesis. This review outlines the current understanding of reactive oxygen species generation and their role in cardiovascular pathophysiology, including atherogenesis, acute myocardial infarction, and congestive heart failure. RECENT FINDINGS: Recent studies highlighting endothelial dysfunction as a response to oxidative stress are of particular interest, as are the findings linking myocardial lipid accumulation (cardiac lipotoxicity) and peroxidation to congestive heart failure. Finally, newer methods to detect reactive oxygen species, including urine assays for measurement of 8,12 iPGF2alpha VI along with nuclear magnetic resonance, can help quantitate the reactive oxygen species burden noninvasively. SUMMARY: The body of current evidence from in vitro studies indicates that oxidative stress plays a major role in cardiovascular disease but the details of molecular events in vivo and in particular in humans remains to be determined. This could partly explain the failure of antioxidant therapy in preventing cardiovascular morbidity and mortality in major clinical trials. The emerging technologies, including MRI, can help delineate the events leading to reactive oxygen species generation and dissipation in humans, and potentially provide a more precisely targeted therapy for the population at risk.

Acute Disease↗

PubMedDate not supplied

[Uncontrolled arterial hypertension: pharmaco-economic interest of hospital diagnostic work-up].

UNLABELLED: The aim of this study was to assess both the clinical usefulness and the economical efficiency of an in-hospital workup for patients with uncontrolled arterial hypertension. PATIENTS AND METHODS: Eligible patients were hospitalized in a specialized unit between 1st January 1998 and 30th June 2000 for management of an uncontrolled arterial hypertension, to general practitioners (GPs) request. A questionnaire was sent to each of these GPs in May 2001. RESULTS: The cohort consisted of 214 patients (107 male, 107 female, mean age: 58 +/- 16 years). Pre-hospitalisation therapy was precisely identified in 178 patients. Forty-nine patients (28%) were given more than 3 antihypertensive drugs. The most frequently administered drugs were the following: diuretics (n = 93), beta-blockers (n = 85), and ACE-inhibitors (n = 78). Mean therapy cost was 1.71 +/- 1.05 [symbol: see text]. An etiology was found in 30 patients (14%). Plasma renin was measured in 140 out of the 184 patients with essential hypertension: it was found as low (< or = 7 ng/L) in 96 patients, with 50 of them (36%) having a very low plasma renin (< or = 3 ng/L). One hundred and fifty-four questionnaires were fulfilled by the GPs. Median follow-up was 23 months. Seventeen patients were lost of follow-up. Nine cardiovascular events were listed. Mean clinic BP was < 160/95 mmHg in 86 out of the 108 patients with both an essential hypertension and a fulfilled questionnaire, including 38 patients (35%) with a clinic BP < 140/90 mmHg. Eleven patients only, were given more than 3 antihypertensive drugs. The most frequently administered drugs were: calcium antagonists (73%), followed by diuretics (50%) and beta-blockers (34%). Mean therapy cost was 1.39 +/- 0.76 [symbol: see text] (p < 0.002 vs pre-hospitalization therapy cost); 84% of the GPs answered that the in-hospital workup resulted in an useful help in managing their patients. CONCLUSION: The in-hospital workup of patients with uncontrolled hypertension turned out to be both clinically useful and economically efficient: an aetiology has been found in 14% of the cases; an appropriate therapy, based on the hormonal profile, allowed for a lowering of BP below 160/95 in 80% of the cases, and below 140/90 in one thirds of the patients; the mean therapy cost has been reduced by 19%.

Adult↗

PubMed1993

Laser conization for microinvasive carcinoma of the cervix. Short-term results.

Thirty-one patients with microinvasive carcinoma of the uterine cervix (less than 3.0 mm invasion, no lymph vascular involvement), were treated with combination laser conization. The mean follow-up period was 36 months. No cases of invasive disease have been diagnosed during follow-up. Examination during follow-up revealed atypical columnar epithelium in one case, but the hysterectomy specimen was normal. Based on these short-term results, combination laser conization for microinvasive carcinoma of the cervix seemed a sufficient therapy. A precise and careful histopathologic evaluation, and the patient acceptance of a strict follow-up schedule are mandatory to a decision to employ conservative management of microinvasive cervical carcinoma. Only long-term follow-up in patients treated by conservative therapy will be able to finally justify this approach.

Journal Article↗

PubMed1991

Ultrasound guided therapeutic catheters: recent developments and clinical results.

The increasing use of intravascular ultrasound technology by clinicians is providing detailed and immediate information about the results of interventions, and this is stimulating the development of new catheters that use ultrasound imaging to control therapy in real time. Cold and thermal balloon angioplasty, atherectomy, embolectomy, laser ablation and rotational recanalization are a few of the interesting capabilities now being added to ultrasound catheters. We report on the development and characteristics of some of these devices and attempt to assess their potential to precisely direct therapy.

Angioplasty, Balloon↗

PubMed1994

Intraperitoneal cisplatin and carboplatin in the management of ovarian cancer.

The intraperitoneal delivery of cisplatin or carboplatin in the management of ovarian cancer is based on a sound pharmacokinetic rationale. Objective responses, including surgically documented complete responses, have been observed in patients with ovarian cancer who have previously responded to systemic platinum-based therapy. A precise role for intraperitoneal cisplatin or carboplatin in the management of ovarian cancer remains to be defined.

Carboplatin↗

PubMed2000

Ultrasound-based stereotactic guidance of precision conformal external beam radiation therapy in clinically localized prostate cancer.

OBJECTIVES: Use of external beam radiation fields that conform to the shape of the target improves biochemical control in prostate cancer by facilitating dose escalation through increased sparing of normal tissue. By correcting potential organ motion and setup errors, ultrasound-directed stereotactic localization is a method that may improve the accuracy and effectiveness of current conformal technology. The purpose of this study was to quantify the precision of the transabdominal ultrasound-based approach using computed tomography (CT) as a standard. METHODS: Thirty-five consecutive men participated in a prospective comparison of daily CT and ultrasound-guided localization at Fox Chase Cancer Center. Daily CT prostate localization was completed before the delivery of each final boost field. In the CT simulation suite, transabdominal ultrasound-based stereotactic localization was also performed. The main outcome measure was a three-dimensional comparison of prostate position as determined by CT versus ultrasound. RESULTS: Sixty-nine daily CT and ultrasound prostate position shifts were recorded for 35 patients. The magnitude of difference between the CT and ultrasound localization ranged from 0 to 7.0 mm in the anterior/posterior, 0 to 6.4 mm in the lateral, and 0 to 6.7 mm in the superior/inferior dimension. The corresponding directed average disagreements were extremely small: anterior/posterior, -0.09 +/- 2.8 mm SD; lateral, -0.16 +/- 2.4 mm SD; and superior/inferior, -0.03 +/- 2.3 mm SD). Analysis of the paired CT-ultrasound shifts revealed a high correlation between the two modalities in all three dimensions (anterior/ posterior r = 0.88; lateral r = 0.91; and superior/inferior r = 0.87). CONCLUSIONS: Ultrasound-directed stereotactic localization is safe and as accurate as CT scanning in targeting the prostate for conformal external beam radiation therapy. The application of this technology to current conformal techniques will allow the reduction of treatment margins in all dimensions. This should diminish treatment-related morbidity and facilitate further dose escalation, resulting in improved cancer control.

Follow-Up Studies↗

PubMed2005

Pathway-specific profiling identifies the NF-kappa B-dependent tumor necrosis factor alpha-regulated genes in epidermal keratinocytes.

Identification of tumor necrosis factor alpha (TNF alpha) as the key agent in inflammatory disorders led to new therapies specifically targeting TNF alpha and avoiding many side effects of earlier anti-inflammatory drugs. However, because of the wide spectrum of systems affected by TNF alpha, drugs targeting TNF alpha have a potential risk of delaying wound healing, secondary infections, and cancer. Indeed, increased risks of tuberculosis and carcinogenesis have been reported as side effects after anti-TNF alpha therapy. TNF alpha regulates many processes (e.g. immune response, cell cycle, and apoptosis) through several signal transduction pathways that convey the TNF alpha signals to the nucleus. Hypothesizing that specific TNF alpha-dependent pathways control specific processes and that inhibition of a specific pathway may yield even more precisely targeted therapies, we used oligonucleotide microarrays and parthenolide, an NF-kappa B-specific inhibitor, to identify the NF-kappa B-dependent set of the TNF alpha-regulated genes in human epidermal keratinocytes. Expression of approximately 40% of all TNF alpha-regulated genes depends on NF-kappa B; 17% are regulated early (1-4 h post-treatment), and 23% are regulated late (24-48 h). Cytokines and apoptosis-related and cornification proteins belong to the "early" NF-kappa B-dependent group, and antigen presentation proteins belong to the "late" group, whereas most cell cycle, RNA-processing, and metabolic enzymes are not NF-kappa B-dependent. Therefore, inflammation, immunomodulation, apoptosis, and differentiation are on the NF-kappa B pathway, and cell cycle, metabolism, and RNA processing are not. Most early genes contain consensus NF-kappaB binding sites in their promoter DNA and are, presumably, directly regulated by NF-kappa B, except, curiously, the cornification markers. Using siRNA silencing, we identified cFLIP/CFLAR as an essential NF-kappa B-dependent antiapoptotic gene. The results confirm our hypothesis, suggesting that inhibiting a specific TNF alpha-dependent signaling pathway may inhibit a specific TNF alpha-regulated process, leaving others unaffected. This could lead to more specific anti-inflammatory agents that are both more effective and safer.

Amino Acid Motifs↗

PubMed2002

Baculovirus as mammalian cell expression vector for gene therapy: an emerging strategy.

The monopoly of insect cells to host baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) as a eukaryotic gene expression system has been shattered with the growing evidence that it also infects mammalian cells in culture. Although AcMNPV fails to replicate in vertebrate cells, it does express alien genes with levels of expression that are dependent on the strength of the promoter used to drive transcription of the foreign gene. It also has been reported that the recombinant AcMNPV enters human hepatic cells in culture preferentially and specifically in comparison with the other mammalian cells of different origin and sources. This has resulted in the use of AcMNPV as a potent mammalian cell delivery system as a xenovector for gene therapy, more precisely liver-specific gene delivery in vitro and in vivo.

Animals↗

PubMed1996

Monocyte-platelet function and protection against cardiovascular disease.

Observational studies reveal a cardioprotective effect of hormone replacement therapy. The precise mechanisms whereby this treatment influences disease risk are not fully understood. Much attention has been paid to changes in lipid and lipoprotein metabolism, but this explains only part of the protective effect. In this short review, the roles of monocyte and platelet function in atherogenesis and thrombus formation are discussed. It is shown that hormone replacement therapy favourably down-regulates monocyte and platelet reactivity, which may be important in explaining the beneficial effect on the risk of cardiovascular disease.

Adult↗

PubMed2000

Lumbar herniated disks.

Patients with low back and leg pain require careful evaluation and it is essential that there is correlation between the symptoms and signs of sciatica and the imaging demonstration of nerve root compression or displacement by a disk herniation before invasive therapy is undertaken. The natural history of herniations of the nucleus pulposus is complex and the relationship between the appearances on imaging and low back and radicular pain still has to be completely resolved. Considerable experimental work has been undertaken on the relationship between nerve compression, inflammation, and pain and recent studies on cytokines may lead to more precise pharmacologic therapies. The prime value of MR imaging may be in monitoring disk and nerve root changes in longitudinal studies of patients randomized to different therapeutic programs.

Contrast Media↗

PubMed2003

The treatment of glomerular disease--a compromise between the standard and the individual approach.

Chronic glomerulonephritis (GN) is one of the leading causes of end-stage renal disease (ESRD). The possibilities for successful treatment in the earliest stages are still limited. Immunosuppressive treatment leads to complete or partial remission only in some patients. Even then, a non-immunological evolution to chronic renal insufficiency often enters a progressive course. By applying a consistent strategy for their individual evaluation and management, it is possible to improve the outcome of patients with GN. The early referral to a nephrologist and an early histomorphological diagnosis; the precise assessment of the type of injury, i.e. proliferative or non-proliferative; the indices of activity and chronicity; and the prognostic indicators are helpful for the therapeutic approach. The goal of the management of GN has to be to suppress the disease with minimum side effects of the treatment. Many unanswered questions and controversies remain concerning the immunosuppressive therapy. A precise distinction is needed between the problematic assertions and evidence-based protocols. A common task for the treatment of all types of chronic GN should be the protection of renal structure and function: control of blood pressure, action on renal haemodynamics and proteinuria via pharmacological inhibition of the renin-angiotensin system, control of hyperlipidaemia and limitation of fibrosis. Some novel and promising pharmacological approaches to extracellular matrix accumulation and chronic interstitial fibrosis are in progress.

Antihypertensive Agents↗

PubMed2026

Discovery and Engineering of a Rat Endogenous Retrovirus Reverse Transcriptase for Efficient Prime Editing.

CRISPR-based prime editors (PEs) install precise edits into genomic DNA without generating double-strand breaks. Their editing efficiency is highly dependent on reverse transcriptases (RTs), but efficient RT candidates remain limited. Here, we identified 19 novel active RTs by screening 558 candidates. Among them, RERV-RT, derived from Rattus norvegicus, exhibited the highest activity. Through structure-guided engineering and deep mutational scanning, we developed an optimized variant, enRERV-RT, which outperforms conventional M-MLV-RT-based PE systems by 1.20-fold in mammalian and plant cells, and by 1.88-fold at hard-to-edit loci, while enabling precise multiplex editing of functionally relevant genes. Additionally, we developed a high-throughput platform, TRAP-seq-PE, to systematically evaluate prime editor performance. Across diverse mutation types, we found that PE systems based on enRERV-RT exhibited higher editing efficiencies than those based on M-MLV-RT. Collectively, our work establishes a versatile, high-efficiency PE system, thereby facilitating advances in clinical gene therapy and precise crop breeding.

Animals↗

PubMed1984

Economics of antihypertensive therapy.

Antihypertensive therapy has come a long way in the past 40 years. With the wide range of drugs now available, cost has become an additional consideration in selection of therapy. However, precise figures for comparison of drugs within and between classes can be difficult and time-consuming to gather. The unit-cost tables in this article are presented with the hope that they will simplify the selection process. Of course, unit cost is not the sole criterion to be considered; potency and frequency of administration also influence the overall cost of therapy.

Adrenergic beta-Agonists↗

PubMed1999

[Current status and future prospects of 3D treatment planning in radiation therapy, focusing on IMRT].

The ultimate goal of radiation therapy is to confine a high dose to the target area while sparing the surrounding normal structures in order to increase the delivered dose and decrease the likelihood of organ injuries. In Japan, the rotational conformal technique, which is a combination of gantry rotation and dynamic movement of multi-leaf collimators (MLC), has been widely used as a standard method for high-precision radiation therapy. The non-coplanar technique in which radiation beams are given in three dimensions has the advantage of dose concentration as well as organ sparing. In intensity modulated radiotherapy (IMRT), an uneven intensity map within a beam is generated with various methods such as "sliding window technique" and "stop and shoot technique". Several intensity modulated beams are combined to create arbitrary dose distribution including concave distribution. Although a substantial number of proton therapy facilities are planned in this country, IMRT should be considered as a competitive rival from the viewpoint of cost-benefit analysis as well as clinical effectiveness.

Humans↗

PubMed2002

Chemotherapy and high-dose-rate brachytherapy in the management of advanced cancers of the nasopharynx: clinical impact of high technology--is it worth the cost?

PURPOSE: The aim of this study was to calculate the costs of chemotherapy and high-dose-rate brachytherapy in advanced-stage nasopharyngeal cancer. It is argued whether the effect of chemotherapy and this type of high-dose, high-precision radiation therapy is worth the costs. METHODS AND MATERIALS: Clinical results of Stage III-IVB nasopharyngeal cancer in patients treated between 1991 and 2000 are reported. Treatment was broken down into five categories: workup, chemotherapy, preparation of radiation therapy, and application of radiation. For each category, costs were computed. Nasopharyngeal cancer treatment costs were compared with costs previously reported on patients treated for cancers of the oral cavity, larynx, and oropharynx. RESULTS: With the addition of neoadjuvant chemotherapy and high cumulative doses of radiation (77-81 Gy) with brachytherapy, disease-free survival increased from 48% to 74% (p=0.002), and overall survival increased from 35% to 72% (p=0.005). The Rotterdam protocol has been implemented stepwise: as of 1991, costs per patient increased from 4521 Euros (US$5023; 2001 exchange rate [December]: 1 Euro approximately 0.88 US$) for conventional external beam radiation therapy to 13,728 Euros (US$15,253) in 2000 for combinations of chemotherapy, conventional external beam radiation therapy, and brachytherapy. In case of stereotactic radiotherapy, the cost was 14,516 Euros (US$16,495). CONCLUSIONS: Costs for cancer in the nasopharynx vary from 14,528 Euros (US$16,509) to 15,316 Euros (US$17,405) in case of brachytherapy and stereotactic radiotherapy, respectively, if follow-up costs are added. The treatment cost for other head and neck sites was 21,858 Euros (US$24,126). Given the improvement in survival, the sparing capabilities of current high-dose, high-precision radiotherapy techniques, and the favorable cost profile compared with other sites, it is argued that costs should not be considered prohibitive for the introduction of chemotherapy and high-technology-based radiotherapy in advanced nasopharyngeal cancer.

Brachytherapy↗