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Biomedical subjects

H J Knowles

Publications and source records attributed to H J Knowles.

10 recordsLinked to original sources
PubMed2001

Hypoxia and oxidative stress in breast cancer. Hypoxia and tumourigenesis.

The microenvironmental hypoxia that arises as a consequence of the development of a solid tumour also acts to promote tumour growth. Hypoxia induces the expression of key components of the angiogenic and apoptotic signalling cascades, the glycolytic pathway and various cell-cycle control proteins. At the cellular level it mediates the infiltration and accumulation of tumour-associated macrophages within avascular tumour regions. Complex interactions between tumour cell and macrophage hypoxia-regulated gene products and their associated pathways form the basis for the hypoxic promotion of tumourigenesis and malignant progression.

Apoptosis↗
PubMed2000

An open-label pilot trial of cladibrine (2-cholordeoxyadenosine) in patients with primary sclerosing cholangitis.

Cladribine (2-chlorodeoxyadenosine) is a nucleoside analog with specific antilymphocytic activity that has been used in patients with a variety of lymphoid malignancies and autoimmune diseases. Primary sclerosing cholangitis (PSC) is a chronic hepatic autoimmune disorder of unknown etiology, thought to be mediated by biliary autoreactive cytotoxic lymphocytes. Because cladribine is an effective antilymphocytic drug, it may have potential disease-modifying activity in patients with PSC. We studied four patients with stages I and II PSC in an open-label pilot trial of 6 months' duration and 2 years' follow-up. Drugs were administered at 0.1 mg/kg/d subcutaneously for 5 days per monthly cycle for a total of 3 cycles. Patients evaluation included monthly liver panel test, cell count and lymphocytes subset, symptom severity score, posttreatment liver biopsy, and endoscopic retrograde cholangiopancreatography at 6 months and 2 years. All patients had a significant decrease in peripheral total lymphocyte (1,629 +/- 462 to 426 +/- 57; p < 0.01) and CD4 cell count (782 +/- 200 to 144 +/- 21; p < 0.05) with consequent decrease of CD4:CD8 ratio (3.82 +/- 1.96 to 1.84 +/- 0.69; p = 0.09). This was associated with a quantifiable decrease in the hepatic inflammatory infiltrate on liver biopsy. No significant changes were found in symptom scores, liver panel tests, or cholangiograms. The drug was well-tolerated and two of four patients reported remission of their inflammatory bowel disease symptoms. Cladribine decreases the hepatic lymphocytic inflammatory infiltrate in early-stage PSC, which did not translate into any short-term symptomatic, biochemical, or radiologic improvements. Further studies with long-term follow-up are needed to assess if this anti-inflammatory effect can modify the progression of disease.

Adult↗
PubMed1998

Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry.

Winged helix transcription factors play important roles in cellular differentiation and cell-specific gene expression. To define the role of the winged helix factor hepatocyte nuclear factor/forkhead homologue (HFH)-4, a targeted mutation was created in the mouse hfh-4 gene. No expression of HFH-4 was detected in hfh-4(-)/- mice by RNA blot analysis, in situ hybridization, or RT-PCR. hfh-4(-)/- mice were noted to have abnormalities of organ situs consistent with random determination of left-right asymmetry. In addition, a complete absence of cilia was noted in hfh-4(-)/- mice. The hfh-4 gene is thus essential for nonrandom determination of left-right asymmetry and development of ciliated cells. Homozygous mutant mice also exhibited prenatal and postnatal growth failure, perinatal lethality and, in some cases, hydrocephalus. RT-PCR revealed an absence of left-right dynein (lrd) expression in the embryonic lungs of hfh-4(-)/- mice, suggesting that HFH-4 may act by regulating expression of members of the dynein family of genes. The abnormalities in ciliary development and organ situs in hfh-4(-)/- mice are similar to those observed in human congenital syndromes such as Kartagener syndrome. Targeted mutation of hfh-4 thus provides a model for elucidating the mechanisms regulating ciliary development and determination of left-right asymmetry.

Abnormalities, Multiple↗
PubMed1996

New interventions in cerebrovascular disease: the role of thrombolytic therapy and balloon angioplasty.

The use of thrombolytic agents (plasminogen activators) in the early moments of ischemic stroke to achieve recanalization and potential neurologic improvement has been actively studied over the past 10 years. In the same period, endovascular techniques for cerebral revascularization have evolved significantly. Recent phase III studies, following angiography-based phase I and II studies of plasminogen activators in stroke, have described evidence of clinical benefit and contributors to morbidity (i.e., symptomatic hemorrhage) and mortality that limit the applicability of this approach. The limited formalized experience with percutaneous transluminal balloon angioplasty and stent placement in the carotid artery and cerebral circulation has given rise to concerns about the safety and appropriateness of the procedures in this territory. However, several prospective series support the feasibility of well-designed clinical trials.

Angioplasty, Balloon↗
PubMed1994

Changing practice patterns in peripheral arterial disease.

The development of interventional radiologic techniques during the past decade has changed our approach to the treatment of lower extremity peripheral arterial disease (LE-PAD). Balloon and laser-assisted angioplasty, atherectomy (rotary and directional devices), stent implantation, and thrombolysis as well as combinations of all of these approaches, at times with concomitant or secondary surgery, have been used in our institution. A review of our practice patterns during the past 5 years was performed to analyze changing attitudes and results with these newer techniques. All new patients seen in consultation for LE-PAD during three alternate years were reviewed with regard to demographics, initial complaints, initial treatment modality, initial outcome, indications for and results of secondary treatment, and ultimate outcome (at 1 year). The 603 patients were seen during the following three 12-month periods: 1987 to 1988, 1989 to 1990, and 1991 to 1992. An intention-to-treat analysis revealed (1) the number of patients seen for peripheral arterial disease has increased steadily; (2) in the last year more were initially treated with intervention as the primary modality; (3) the results of such catheter-based procedures improved only slightly over this 5-year period, despite our learning curve and the fact that we discarded several ineffective interventional approaches; (4) the fraction of patients primarily operated on and the excellent results of surgery have not changed; and (5) the number of operations for proximal (aortoiliac) disease has decreased markedly, with a corresponding increase in distal reconstructions. The evolution of our current approach to the treatment of LE-PAD is based on this continuing experience.

Angioplasty, Balloon↗
PubMed1993

Initial experience with the Palmaz stent for aortoiliac stenoses.

The initial 37 consecutive patients to be treated at our institution with the Palmaz stent placed in the aortoiliac arteries were retrospectively reviewed. In these patients, 50 stenoses and six occlusions were treated with 128 stents. Nine patients with combined iliac and common femoral obstruction underwent common femoral endarterectomy and profoundaplasty with intraoperative iliac artery angioplasty and stent application. Stenoses were reduced from 57 +/- 17% to 1 +/- 5% (p < 0.01), and peak systolic pressure gradients across the lesions were reduced from 45 +/- 30 mm Hg to 1.3 +/- 3.4 mm Hg (p < 0.01). Symptoms resolved in 27 patients and improved in eight patients. One patient died and four patients were treated nonoperatively for complications. During a mean follow-up of 12 months (6 to 21 months), six patients had recurrence of symptoms (16%) and four patients died of other diseases. Routine arteriograms after 6 months in 19 patients demonstrated recurrent mild to moderate stenoses (9% to 43%) in six patients (32%), but only two were symptomatic (11%). Secondary procedures included reexpansion of aortic and iliac stents in two patients and aortofemoral bypass in two patients. Early results suggest the efficacy of the Palmaz stent in the management of aortoiliac stenoses and its use intraoperatively in conjunction with surgical correction of outflow. Close follow-up of these patients by multidisciplinary groups is warranted.

Adult↗
PubMedDate not supplied

Identification of differentially expressed genes in experimental models of the tumor microenvironment using differential display.

BACKGROUND: Genes upregulated within the tumour microenvironment represent potential targets for rational drug design. Most studies to date concentrate on the effects of hypoxia, although it is likely many genes are regulated by a more physiological combination of factors. MATERIALS & METHODS: Cells under conditions analogous to the normal and tumour microenvironments were isolated from the plateau-phase system and multicellular spheroids. Gene expression was analysed by differential display and confirmed by Northern blot or semiquantitative RT-PCR. RESULTS: p21-activated kinase (PAK1), a calmodulin-related mRNA, cytochrome oxidase subunit I and an H3.3 histone were upregulated within the in vitro tumour microenvironment, the last 3 within spheroids. CONCLUSIONS: Both models exhibit a range of microenvironmental parameters, although spheroids are more physiological with respect to the presence of extreme hypoxia and the formation of 3-dimensional interactions. We have shown that it is feasible to manipulate the spheroid system by serial trypsinisation to obtain reproducible cell populations for gene expression studies.

Adenocarcinoma↗