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Biomedical subjects

M A Hoffman

Publications and source records attributed to M A Hoffman.

At least 19 recordsLinked to original sources
PubMed2006

The genome-enabled electronic medical record.

The integration of patient-specific genomic information into the electronic medical record (EMR) will create many opportunities to improve patient care. Key to the successful incorporation of genomic information into the EMR will be the development of laboratory information systems capable of appropriately formatting molecular diagnostic and cytogenetic findings in the EMR. Due to the lack of granular genomics-related content in existing medical vocabularies, the adoption of new standards for describing clinically significant genomic information will be an important step toward recognizing the genome-enabled EMR. Appropriate capture of patient-specific genomic results in the EMR will generate new opportunities to utilize this information in clinical decision support, including automated response to pharmacogenomic-based risks.

Computational Biology↗
PubMed2005

Durable response of metastatic endometrial carcinoma to treatment with fulvestrant (Faslodex) after prior progestin and anastrozole therapy.

BACKGROUND: Patients with metastatic endometrial carcinoma may respond to hormonal therapy with progestins. There is a need for new therapies for hormone-responsive disease. CASE: We report a patient with metastatic endometrial carcinoma to the lungs, who after progressing on progestin therapy, had a lengthy remission with anastrozole; upon further progression, fulvestrant (Faslodex) was instituted, with a resultant partial remission, which has been sustained for almost 3 years. CONCLUSION: In this case, fulvestrant therapy was successful even in the face of prior anastrozole and megestrol. The activity of fulvestrant in patients with metastatic endometrial carcinoma should be further explored, especially in situations in which the tumor is well differentiated and/or expresses hormone receptors.

Aged↗
PubMed2004

Arthrogenic muscle response to a simulated ankle joint effusion.

BACKGROUND: Arthrogenic muscle inhibition (AMI) is a continuing reflex reaction of the musculature surrounding a joint after distension or damage to the structures of that joint. This phenomenon has been well documented after knee joint injury and has been generalised to occur at other joints of the human body, yet minimal research has been conducted in this regard. The response of the muscles crossing the ankle/foot complex after ankle injury and effusion is not well understood. AMI may occur after an ankle sprain contributing to residual dysfunction. OBJECTIVE: To determine if AMI is present in the soleus, peroneus longus, and tibialis anterior musculature after a simulated ankle joint effusion. METHODS: Eight neurologically sound volunteers (mean (SD) age 23 (4) years, height 171 (6) cm, mass 73 (10) kg) participated. Maximum H-reflex and maximum M-wave measurements were collected using surface electromyography after delivery of a percutaneous stimulus to the sciatic nerve before its bifurcation into the common peroneal and posterior tibial nerves. RESULTS: The H-reflex and M-wave measurements in all muscles increased (p< or =0.05) after the simulated ankle joint effusion. CONCLUSIONS: Simulated ankle joint effusion results in facilitation of the soleus, peroneus longus, and tibialis anterior motoneurone pools. This may occur to stabilise the foot/ankle complex in order to maintain posture and/or locomotion.

Adult↗
PubMed2003

Genetic stability of attenuated mengovirus vectors with duplicate primary cleavage sequences.

Short poly(C)-tract Mengoviruses have proven vaccine efficacy in many species of animals. A novel vector for the delivery of foreign proteins was created by insertion of a second autoproteolytic primary cleavage cassette linked to a multiple cloning site (MCS) into an attenuated variant of Mengo. Nineteen cDNAs from foreign sequences that ranged from 39 to 1653 bases were cloned into the MCS. The viral reading frame was maintained and translation resulted in dual, autocatalytic excision of the foreign peptides without disruption of any Mengo proteins. All cDNAs except those with the largest insertions produced viable virus. Active proteins such as GFP, CAT, and SIV p27 were expressed within infected cells. Relative to parental Mengo, the growth kinetics and genetic stability of each vector was inversely proportional to the size of the inserted sequence. While segments up to 1000 bases could be carried, inserts greater than 500-600 bases were usually reduced in size during serial passage. The limit on carrying capacity was probably due to difficulties in virion assembly or particle stability. Yet for inserts less than 500-600 bases, the Mengo vectors provided an effective system for the delivery of foreign epitopes into cells and mice.

Animals↗
PubMed2002

Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous etoposide solution.

OBJECTIVE: To compare the release of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags from four different manufacturers into intravenous etoposide solutions. METHOD: Etoposide solutions, 0.4 mg/mL, containing the vehicle polysorbate 80 were prepared in 5% dextrose or 0.9% sodium chloride injection PVC bags and stored at room temperature for 24 h. DEHP content was analysed by high-performance liquid chromatography. RESULTS: Substantial amounts of DEHP (up to 20 microg/mL at room temperature) leached into the etoposide solutions. However, no significant differences were found in the amounts of DEHP leached into the etoposide infusion solutions prepared using either 5% dextrose or 0.9% sodium chloride injection and stored in the four different containers. CONCLUSION: To minimize patient exposure o DEHP, etoposide solutions should ideally be stored in a glass or polyolefin container.

Antineoplastic Agents, Phytogenic↗
PubMed2001

von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF.

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germ line mutation of the von Hippel-Lindau tumor suppressor gene (VHL). Tumors observed in this disorder include retinal and central nervous system hemangioblastomas, clear cell renal carcinomas and pheochromocytomas. The VHL gene product, pVHL, is a component of a ubiquitin ligase which targets the transcription factor known as hypoxia-inducible factor (HIF) for degradation in the presence of oxygen. pVHL also plays roles in the control of extracellular matrix formation and cell-cycle exit. Different VHL mutations confer different site-specific risks of cancer. Type 2C VHL mutations confer an increased risk of pheochromocytoma without the other stigmata of VHL disease. Here we report that the products of such type 2C VHL alleles retain the ability to down regulate HIF but are defective for promotion of fibronectin matrix assembly. Furthermore, pVHL L188V, a well studied type 2C mutant, retained the ability to suppress renal carcinoma growth in vivo. These studies strengthen the notion that HIF deregulation plays a causal role in hemangioblastoma and renal carcinoma, and raises the possibility that abnormal fibronectin matrix assembly contributes to pheochromocytoma pathogenesis in the setting of VHL disease.

Alleles↗
PubMed2001

A phase II trial of CI-958 in recurrent platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study.

OBJECTIVES: To estimate the antitumor efficacy of CI-958 in patients with measurable recurrences of platinum-sensitive ovarian carcinoma and to determine the nature and degree of toxicity of CI-958 in these patients. METHODS: Patients received CI-958 560 mg/m2 intravenously every 3 weeks and tumor measurements were performed every one to two cycles. RESULTS: Of 23 patients entered in the study, there was one complete response and 10 patients had stable disease with short response durations. CONCLUSIONS: CI-958 has minimal activity in recurrent platinum-sensitive ovarian carcinoma at the dose and schedule tested.

Adult↗
PubMed2001

Postural control: visual and cognitive manipulations.

Numerous questions exist regarding the utilization of sensory information for postural control. Past research has established the possibility that cognitive tasks requiring visual perception may affect the processing of visual information used for postural control. The purpose of this study was two fold: (1) to investigate the effects of varying demands of visual perception and (2) to evaluate the effects of performing a cognitive task on postural control in healthy, young adults (N=30). Three posture-related dependent variables were recorded during the manipulation of two independent variables (eye movement and modality of presentation of a cognitive task). The two levels of eye movement were movement and no movement, while the three levels of modality of presentation were visual, auditory, and none. A 2x3 repeated measures ANOVA was applied to the data to investigate the presence of group differences. Significantly more variability was observed in the no cognitive condition than the visual and the auditory for medial-lateral (M--L) COP variability. Additionally, the eye movement condition revealed significantly greater M--L COP variability than the no eye movement condition. No differences were observed between the visual and auditory conditions for any dependent variable. Therefore, the greatest COP variability was observed in the eye movement and no cognitive condition. Further, an interesting relationship between the measures of COP variability and sway velocity was described.

Adult↗
PubMed2000

Analysis of RNA secondary structure in replication of human parainfluenza virus type 3.

The terminal RNA regions of the genomic and antigenomic RNAs of the paramyxoviruses and rhabdoviruses are known to contain sequences essential for RNA replication and transcription. The 3'- and 5'-termini of human parainfluenza virus type 3 (HPIV3) genomic RNA, termed leader and trailer sequences, respectively, are capable of forming stable stem-loop structures. Additionally, the 17 terminal bases of the leader and trailer are complementary and therefore also capable of forming a helical structure. We investigated the roles of the stem-loop structure and terminal complementarity in HPIV3 RNA replication and transcription in vivo using a minigenome containing all RNA elements necessary for these processes. By mutational analysis, we show that the RNA secondary structure features present at the termini of HPIV3 have no discernible role in replication or transcription. Rather, the primary sequence of these regions is what is critical in promoting replication. Interestingly, a mutation at leader base 24 was found to revert a mutation at leader position 5 but probably not via RNA secondary structure restoration.

Base Pairing↗
PubMed2000

Precise mapping of the replication and transcription promoters of human parainfluenza virus type 3.

The terminal RNA regions of the genomic and antigenomic RNAs of the paramyxoviruses and rhabdoviruses are known to contain sequences essential for directing RNA replication and transcription. The 3' terminus (leader region) of the negative-sense, genomic RNA of the rhabdoviruses and paramyxoviruses is known as the leader (Le) promoter and directs synthesis of positive-sense replication and transcription products. The 3' terminus of the antigenome is termed the trailer complementary (TrC) promoter and directs the synthesis of genomic RNA. By creating mutations in the corresponding regions of an HPIV3 minireplicon in which the viral protein coding sequences were replaced by the luciferase gene, we were able to precisely define the elements of the leader promoter involved in directing positive-strand replication of HPIV3. Nucleotides 1 through 12 (from the terminus) formed a domain critical for replication. The region from nucleotides 13 through 55 was important but not crucial for replication, while G residues at positions 79, 85, and 91 comprised another domain critical for replication. It was also shown that the TrC promoter is similar, though not identical, to the Le promoter. Nucleotides 1 through 12 of the TrC promoter were critical for synthesis of genomic RNA, though specific positions behaved differently from the corresponding positions of the Le promoter. While many of these mutations could not be analyzed for transcription because they completely abrogated genomic RNA synthesis (the template for transcription), we were surprised to find that no mutations in the leader promoter which decreased replication had any significant effect on transcription. However, mutations in the intergenic sequence and gene start signal following the leader and preceding the luciferase message severely decreased transcription, but not replication.

Base Sequence↗
PubMed2000

Phase II trial of CI-958 in recurrent platinum-refractory ovarian carcinoma. A Gynecologic Oncology Group Study.

OBJECTIVES: The objectives of this study were twofold: (1) to estimate the anti-tumor efficacy of CI-958 in patients with measurable platinum-resistant ovarian cancer; (2) to determine the nature and degree of toxicity of CI-958 in these patients. METHODS: Patients received CI-958 560 mg/m(2) intravenously every 3 weeks and tumor measurements were performed every one to two cycles. RESULTS: In 25 cases with recurrent platinum-resistant disease, there was one partial response (PR) and six patients had stable disease (SD). CONCLUSIONS: CI-958 has minimal activity in platinum-resistant ovarian cancer at the dose and schedule tested.

Adult↗
PubMed2000

Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome that is characterized by the development of multiple vascular tumors and is caused by inactivation of the von Hippel-Lindau protein (pVHL). Here we show that pVHL, through its beta-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an alpha-domain-dependent manner. This is the first function to be ascribed to the pVHL beta-domain. Furthermore, we provide the first direct evidence that pVHL has a function analogous to that of an F-box protein, namely, to recruit substrates to a ubiquitination machine. These results strengthen the link between overaccumulation of HIF and development of VHL disease.

Cell Extracts↗
PubMed2000

Evaluation of cyclin expression in testicular germ cell tumors: cyclin E correlates with tumor type, advanced clinical stage, and pulmonary metastasis.

The measurement of proliferative index has yielded promising yet conflicting results in the evaluation of testicular tumors. We have examined the role of Ki-67, along with the cyclins A and E in testicular tumorigenesis. We compared the immunoreactivity of 20 pure seminomas with 20 mixed germ cell tumors composed predominantly of embryonal carcinoma with a variety of proliferation markers, including Ki-67, cyclin A, and cyclin E. All 40 tumors stained for Ki-67, and 19 of 20 (95%) seminomas and 18 of 20 (90%) embryonal carcinomas stained positively for cyclin A. Cyclin E stained 14 of 19 (74%) of the embryonal carcinomas and only 4 of 20 (20%) of the seminomas (Fisher's exact two-tailed test, P = .0012). There was a trend toward larger tumor size for cyclin E-positive seminomas (median, 5.92 cm versus 3.96 cm; P = .08), although the same correlation was not significant in embryonal carcinomas. For both seminomas and embryonal carcinomas, staining with cyclin E did not correlate with the presence of lymphovascular invasion or capsular invasion. However, patients who had cyclin E-positive tumors presented with higher clinical stage (P = .0015). In addition, pulmonary spread in embryonal carcinomas (four patients) and seminomas (one patient) occurred only in patients whose tumors were cyclin E positive (P = .014). Although Ki-67 and cyclin A offer little prognostic information in testicular germ cell tumors, cyclin E immunoreactivity correlates with tumor type and is strongly predictive of distant tumor spread.

Adult↗
PubMed2000

Early catheter removal in 100 consecutive patients undergoing radical retropubic prostatectomy.

OBJECTIVES: To investigate the outcome of 100 consecutive patients selected for early catheter removal after radical retropubic prostatectomy (RRP), where urethral catheter drainage is used routinely for 2-3 weeks. PATIENTS AND METHODS: The study included 129 consecutive patients with clinically localized prostate cancer who underwent RRP. Catheters were removed in the clinic (with no radiographic studies) 8-9 days after RRP provided there was no evidence of urine leak, pelvic haematoma, rectal injury or severe obesity. The follow-up (mean 21 months) results were available for 118 patients, 100 of whom were candidates for early catheter withdrawal. Their records were reviewed for evidence of complications, including urinary retention, anastomotic stricture formation and urinary incontinence. RESULTS: Urinary retention developed in two of the 100 patients, requiring simple catheter replacement. Nine patients developed bladder neck contracture requiring dilatation or incision. No patients developed anastomotic disruption, urinary tract infection or pelvic abscess. At the mean follow-up of 21 months, 76% of patients were continent and did not require pads; 19% of patients had mild stress urinary incontinence requiring the use of </= 1 pad/day, 4% of patients had incontinence requiring 2-4 pads/day, and 1% of patients required > 4 pads/day. CONCLUSION: With appropriate patient selection as described, catheters can be removed in the clinic (with no radiographic studies) 8-9 days after RRP, with no increased incidence of complications, including anastomotic stricture, retention or incontinence.

Follow-Up Studies↗
PubMed2000

Role of NH(2)- and COOH-terminal domains of the P protein of human parainfluenza virus type 3 in transcription and replication.

The phosphoproteins (P proteins) of paramyxoviruses play a central role in transcription and replication of the viruses by forming the RNA polymerase complex L-P and encapsidation complex (N-P) with nucleocapsid protein (N) and binding to N protein-encapsidated genome RNA template (N-RNA template). We have analyzed the human parainfluenza virus type 3 (HPIV3) P protein and deletion mutants thereof in an in vitro transcription and in vivo replication system. The in vitro system utilizes purified N-RNA template and cell extract containing L and P proteins coexpressed via plasmids using a recombinant vaccinia virus expression system. The in vivo system takes advantage of minigenome replication, which measures luciferase reporter gene expression from HPIV3 minigenomes by viral proteins in a recombinant vaccinia virus expression system. These studies revealed that the C-terminal 20-amino-acid region of P is absolutely required for transcription in vitro and luciferase expression in vivo, suggesting its critical role in viral RNA synthesis. The N-terminal 40-amino-acid region, on the other hand, is essential for luciferase expression but dispensable for transcription in vitro. Consistent with these findings, the C-terminal domain is required for binding of P protein to the N-RNA template involved in both transcription and replication, whereas the N-terminal domain is required for the formation of soluble N-P complex involved in encapsidation of nascent RNA chains during replication. Coimmunoprecipitation analysis showed that the P protein forms a stable homooligomer (perhaps a trimer) that is present in L-P and N-P complexes in the higher oligomeric forms (at least a pentamer). Interestingly, coexpression of a large excess of N- or C-terminally deleted P with wild-type P had no effect on minigenome replication in vivo, notwithstanding the formation of heterooligomeric complexes. These data indicate that P protein with a deleted terminal domain can function normally within the P heterooligomeric complex to carry out transcription and replication in vivo.

Cell Line↗
PubMed2000

Is low serum free testosterone a marker for high grade prostate cancer?

PURPOSE: The association of free and total testosterone with prostate cancer is incompletely understood. We investigated the relationship of serum free and total testosterone to the clinical and pathological characteristics of prostate cancer. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of 117 consecutive patients treated by 1 physician and diagnosed with prostate cancer at our medical center between 1994 and 1997. Low free and total testosterone levels were defined as 1.5 or less and 300 ng./dl., respectively. RESULTS: After evaluating all 117 patients we noted no correlation of free and total testosterone with prostate specific antigen, patient age, prostatic volume, percent of positive biopsies, biopsy Gleason score or clinical stage. However, in patients with low versus normal free testosterone there were an increased mean percent of biopsies that showed cancer (43% versus 22%, p = 0.013) and an increased incidence of a biopsy Gleason score of 8 or greater (7 of 64 versus 0 of 48, p = 0.025). Of the 117 patients 57 underwent radical retropubic prostatectomy. In those with low versus normal free testosterone an increased mean percent of biopsies demonstrated cancer (47% versus 28%, p = 0.018). Pathological evaluation revealed stage pT2ab, pT2c, pT3 and pT4 disease, respectively, in 31%, 64%, 8% and 0% of patients with low and in 40%, 40.6%, 12.5% and 6.2% in those with normal free testosterone (p>0.05). CONCLUSIONS: In our study patients with prostate cancer and low free testosterone had more extensive disease. In addition, all men with a biopsy Gleason score of 8 or greater had low serum free testosterone. This finding suggests that low serum free testosterone may be a marker for more aggressive disease.

Aged↗
PubMed1999

Squamous cell carcinoma of the penis and microscopic pathologic margins: how much margin is needed for local cure?

BACKGROUND: Total or partial penile amputation is an effective treatment for invasive squamous cell carcinoma of the penis. The authors evaluated the relation between paraffin section microscopic pathologic margins and local recurrence. METHODS: Seventeen cases of biopsy proven squamous cell carcinoma of the penis treated with partial or total penectomy were reviewed retrospectively. All resections were performed by one surgeon (K.R.L.). Permanent microscopic pathologic margins and pathologic classification were determined by one pathologist (A.A.R.) using the American Joint Committee on Cancer TNM classification of 1997. RESULTS: Seven of the 10 patients who underwent a partial penectomy were followed for a mean duration of 33.1 months (range, 3-75 months). The average microscopic pathologic margin was 14.4 mm (range, 0-40 mm) for lesions classified as T1 or greater. Three patients had a microscopic margin < or = 10 mm. There were no local or regional recurrences in this group of patients. The 7 patients who underwent a total penectomy were followed for a mean duration of 25.2 months (range, 5-76 months). There were no local recurrences and only one inguinal recurrence. The average microscopic pathologic margin was 14.8 mm (range, 0-50 mm) for all stages. There were 4 patients who had microscopic pathologic margins < or = 10 mm, and all were free of local disease at the last follow-up. CONCLUSIONS: None of the 14 patients followed developed local recurrence. Also, no recurrence occurred in 7 patients who had microscopic margins of < or =10 mm. This suggests that local control can be obtained with margins measuring less than the standard 15-25 mm.

Amputation, Surgical↗