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Michael C Haffner

Publications and source records attributed to Michael C Haffner.

7 recordsLinked to original sources
PubMed2026

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes.

Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.

Journal Article↗
PubMed2006

Characterization of the nuclear factor-kappa B responsiveness of the human dio2 gene.

Type 2 iodothyronine deiodinase (D2) activates T4 by deiodination to T3, a process being the source of most T3 present in the brain. In the mediobasal hypothalamus, expression of the dio2 gene is potently activated by administration of bacterial lipopolysaccharide (LPS), which in turn mediates the modifications in thyroid homeostasis typically observed in patients with nonthyroidal illness syndrome. Here we show that LPS-induced D2 expression is also observed in human MSTO-211H cells that endogenously express D2. Exposure to LPS rapidly doubled D2 activity by a mechanism that was partially blocked by the nuclear factor-B (NF-B) inhibitor sulfasalazine. Next, the human dio2 5'-flanking region promoter assay was used in HC11 cells and the p65/NF-kappa B responsiveness mapped to the 3' approximately 600-bp region of hdio2 5'-flanking region, with an approximately 15-fold induction. Semiquantitative EMSA identified the strongest NF-B binding sites at the positions -683 bp (called no. 2) and -198 bp (no. 5) 5' to the transcriptional starting site. Despite the very similar NF-kappa B binding affinity of these two sites, site-directed mutagenesis and promoter assay indicated that only site no. 5 possessed transactivation potency in the presence of the p65 subunit of NF-kappa B. Other cytokine mediators such as signal transducer and activator of transcription-3 (STAT3) or signal transducer and activator of transcription-5 (STAT5) did not induce transcription of the dio2 gene. Our results indicate that inflammatory signals regulate D2 expression predominantly via the NF-kappa B pathway in a direct transcriptional manner and could contribute to the changes in thyroid economy observed in nonthyroidal illness syndrome during infection.

Animals↗
PubMed2006

Combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes (COMPARE-MS) for the rapid, sensitive and quantitative detection of DNA methylation.

Hypermethylation of CpG island (CGI) sequences is a nearly universal somatic genome alteration in cancer. Rapid and sensitive detection of DNA hypermethylation would aid in cancer diagnosis and risk stratification. We present a novel technique, called COMPARE-MS, that can rapidly and quantitatively detect CGI hypermethylation with high sensitivity and specificity in hundreds of samples simultaneously. To quantitate CGI hypermethylation, COMPARE-MS uses real-time PCR of DNA that was first digested by methylation-sensitive restriction enzymes and then precipitated by methyl-binding domain polypeptides immobilized on a magnetic solid matrix. We show that COMPARE-MS could detect five genome equivalents of methylated CGIs in a 1000- to 10,000-fold excess of unmethylated DNA. COMPARE-MS was used to rapidly quantitate hypermethylation at multiple CGIs in >155 prostate tissues, including benign and malignant prostate specimens, and prostate cell lines. This analysis showed that GSTP1, MDR1 and PTGS2 CGI hypermethylation as determined by COMPARE-MS could differentiate between malignant and benign prostate with sensitivities >95% and specificities approaching 100%. This novel technology could significantly improve our ability to detect CGI hypermethylation.

Animals↗
PubMed2006

Exploiting our knowledge of NF-kappaB signaling for the treatment of mammary cancer.

Nuclear Factor-kappaB (NF-kappaB) has been implicated in the lobuloalveolar development of the mammary gland. In breast cancer its activation has been linked to tumor progression via stimulation of cell proliferation, pro-survival, and angiogenesis pathways and metastasis. Whether NF-kappaB activation in the immune system influences mammary cancer remains unclear. In addition to the constitutive activation frequently found in mammary carcinoma tissue, radio- and chemotherapeutic agents used in the treatment of mammary cancer can lead to activation of NF-kappaB. This effect has been postulated to contribute to the development of resistance to these agents and suggests the use of NF-kappaB inhibitors as sensitizers for therapy. The review describes principle targets and drugs used to inhibit NF-kappaB function and discusses future perspectives in the use of these inhibitors for the treatment of mammary cancer.

Animals↗
PubMed2005

Obesity does not adversely affect health-related quality-of-life outcomes after anatomic retropubic radical prostatectomy.

OBJECTIVES: To study the impact of obesity on the health-related quality-of-life (HRQOL) outcomes after radical prostatectomy (RP). METHODS: Patient-reported sexual and urinary HRQOL was assessed at baseline and 3, 6, 12, and 24 months after anatomic retropubic RP using the University of California, Los Angeles, Prostate Cancer Index among a cohort of 340 men. Linear regression analysis was used to compare the longitudinal HRQOL scores by body mass index (BMI) adjusting for age, baseline HRQOL, and nerve-sparing status (non-nerve sparing versus unilateral versus bilateral). RESULTS: At baseline, the sexual and urinary function and bother scores were similar between normal-weight (BMI less than 25 kg/m2), overweight (BMI 25.0 to 29.9 kg/m2), and obese (BMI 30 kg/m2 or greater) men. Obese men were as likely to undergo bilateral nerve-sparing surgery as men with a lower BMI. After adjustment for age, baseline HRQOL, and nerve-sparing status, no statistically significant differences were found in any HRQOL score at any point among the BMI groups, except for a lower urinary function score at 24 months among overweight men (P = 0.02). CONCLUSIONS: In a select group of men undergoing RP at a tertiary care referral center, BMI was, in general, unrelated to the baseline and longitudinal postoperative HRQOL scores. Obese men (BMI 30 to 35 kg/m2) should not be selectively discouraged against RP because of concerns about HRQOL. Additional studies are needed to assess the HRQOL outcomes among men with very high BMI values (greater than 35 kg/m2).

Body Mass Index↗
PubMed2005

Health-related quality-of-life outcomes after anatomic retropubic radical prostatectomy in the phosphodiesterase type 5 ERA: impact of neurovascular bundle preservation.

OBJECTIVES: To examine the impact of neurovascular bundle preservation on longitudinal health-related quality-of-life (HRQOL) outcomes after anatomic radical retropubic prostatectomy (RP) using a validated questionnaire. METHODS: We examined patient-reported sexual and urinary HRQOL at baseline and at 3, 6, 12, and 24 months after RP using the University of California, Los Angeles, Prostate Cancer Index among 342 patients treated between 2001 and 2004 by a single surgeon. The time to return to baseline urinary and sexual function and bother were compared between men who underwent unilateral versus bilateral nerve-sparing RP using a Cox proportional hazards regression model. RESULTS: Of the 342 patients, 15 (5%), 69 (20%), and 258 (75%) had no, one, or both neurovascular bundles preserved, respectively. After adjustment for age and baseline sexual function, bilateral nerve sparing was associated with greater sexual function scores than unilateral nerve sparing at all points, although the differences only approached or reached significance at 3 (P = 0.06) and 6 (P = 0.04) months after RP. After adjustment for age and baseline sexual function, a trend was noted for an earlier return to baseline sexual function among men who underwent bilateral nerve-sparing RP (hazard ratio 1.67, 95% confidence interval 0.88 to 3.17, P = 0.12), although this did not reach significance. More than 90% of the men returned to their baseline urinary function and bother, regardless of nerve-sparing status. CONCLUSIONS: In the current study, bilateral nerve-sparing RP was associated with better postoperative sexual HRQOL scores than unilateral nerve-sparing RP, although in general the differences were slight.

3',5'-Cyclic-GMP Phosphodiesterases↗