Kate Fisher

PXY, a receptor-like kinase essential for maintaining polarity during plant vascular-tissue development.

All plant tissue is ultimately derived from the meristems, and the molecular mechanisms that control growth of apical meristems have been widely studied (reviewed in). In contrast, much less attention has been paid to vascular meristems, such as the cambium and procambium, even though these meristems are the source of woody tissue and therefore generate the majority of plant biomass. Although biomass may represent a novel source of renewable energy, little is known about the molecular regulation of vascular-meristem activity. The vascular meristems participate in a highly ordered developmental process with a very prominent polarity. This polarity results in precisely orientated divisions of meristematic initials that generate files of cells, which differentiate into highly specialized and spatially separated xylem and phloem cells. The factors that are necessary to establish and maintain this polarity remain unknown. This manuscript describes the identification of the PXY mutant in which the spatial organization of vascular development is lost and the xylem and phloem are partially interspersed. The PXY gene encodes for a receptor-like kinase (RLK) that defines a novel role for RLKs in the meristem where it functions to maintain the cell polarity required for the orientation of cell division during vascular development.

Methylation and demethylation activities of a C. elegans MLL-like complex attenuate RAS signalling.

The conserved Mixed Lineage Leukaemia (MLL) complex deposits activating methyl marks on histone tails through a methyltransferase (MT) activity. Here we provide in vivo evidence that in addition to methylation, the C. elegans MLL-like complex can remove specific methyl marks linked to repression of transcription. This supports the proposed model in which the MLL complex orchestrates both the deposition and the removal of methyl marks to activate transcription. We have uncovered the MLL-like complex in a large-scale RNAi screen designed to identify attenuators of RAS signalling during vulval development. We have also found that the histone acetyltransferase complex, NuA4/TIP60, cooperates with the C. elegans MLL-like complex in the attenuation of RAS signalling. Critically, we show that both complexes regulate a common novel target and attenuator of RAS signalling, AJM-1 (Apical Junction Molecule-1). Therefore, the C. elegans MLL-like complex cooperates with the NuA4/TIP60 complex to regulate the expression of a novel effector, AJM-1.

A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity

The coordinated regulation of mitochondrial and nuclear activities is essential for cellular respiration and its disruption leads to mitochondrial dysfunction, a hallmark of ageing. Mitochondria communicate with nuclei through retrograde signalling pathways that modulate nuclear gene expression to maintain mitochondrial homeostasis. The monooxygenase CLK-1 (human homologue COQ7) was previously reported to be mitochondrial, with a role in respiration and longevity. We have uncovered a distinct nuclear form of CLK-1 that independently regulates lifespan. Nuclear CLK-1 mediates a retrograde signalling pathway that is conserved from Caenorhabditis elegans to humans and is responsive to mitochondrial reactive oxygen species, thus acting as a barometer of oxidative metabolism. We show that, through modulation of gene expression, the pathway regulates both mitochondrial reactive oxygen species metabolism and the mitochondrial unfolded protein response. Our results demonstrate that a respiratory enzyme acts in the nucleus to control mitochondrial stress responses and longevity.

Natural History of Cutaneous Human Papillomavirus (HPV) Infection in Men: The HIM Study

Accumulating evidence suggests that cutaneous human papillomavirus (HPV) infection is associated with non-melanoma skin cancer (NMSC). Little is known about the natural history of cutaneous HPV. A sub-cohort of 209 men with no NMSC history, initially enrolled in the HPV infection in men (HIM) study, were followed for a median of 12.6 months. Epidemiological data were collected through self-administered questionnaires. Cutaneous HPV DNA was measured in normal skin swabs (SS) and eyebrow hairs (EB) for 25 and 16 HPV types in genera β and γ, respectively. Any β HPV infection was more prevalent in SS (67.3%) compared to EB (56.5%, p = 0.04). Incidence in SS was higher than 20 per 1,000 person-months for HPV types 4, 5, 23, 38 and 76. Median duration of persistence of β and γ HPV infection was 8.6 and 6.1 months in EB, respectively, and 11.3 months and 6.3 months, in SS, respectively. Older age (>44 years vs. 18-30 years) was significantly associated with prevalent (SS OR = 3.0, 95% CI = 1.2–7.0) and persistent β HPV infection (EB OR = 6.1, 95% CI = 2.6–14.1). History of blistering sunburn was associated with prevalent (OR = 2.8, 95% CI = 1.3–5.8) and persistent (OR = 2.3, 95% CI = 1.2–4.6) β HPV infection in SS. Cutaneous HPV is highly prevalent in men, with age and blistering sunburn being significant risk factors for cutaneous β HPV infection.

Primary Care Utilization and Colorectal Cancer Incidence and Mortality Among Medicare Beneficiaries: A Population-Based, Case–Control Study

BACKGROUND Utilization of primary care may decrease colorectal cancer (CRC) incidence and death through greater receipt of CRC screening tests. OBJECTIVE To examine the association of primary care utilization with CRC incidence, CRC deaths, and all-cause mortality. DESIGN Population-based, case-control study. SETTING Medicare program. PARTICIPANTS Persons aged 67 to 85 years diagnosed with CRC between 1994 and 2005 in U.S. Surveillance, Epidemiology, and End Results (SEER) regions matched with control patients (n = 205,804 for CRC incidence, 54,160 for CRC mortality, and 121,070 for all-cause mortality). MEASUREMENTS Primary care visits in the 4- to 27-month period before CRC diagnosis, CRC incidence, CRC mortality, and all-cause mortality. RESULTS Compared with persons having 0 or 1 primary care visit, persons with 5 to 10 visits had lower CRC incidence (adjusted odds ratio [OR], 0.94 [95% CI, 0.91 to 0.96]) and mortality (adjusted OR, 0.78 [CI, 0.75 to 0.82]) and lower all-cause mortality (adjusted OR, 0.79 [CI, 0.76 to 0.82]). Associations were stronger in patients with late-stage CRC diagnosis, distal lesions, and diagnosis in more recent years when there was greater Medicare screening coverage. Ever receipt of CRC screening and polypectomy mediated the association of primary care utilization with CRC incidence. LIMITATION This study used administrative data, which made it difficult to identify potential confounders and prevented examination of the content of primary care visits. CONCLUSION Medicare beneficiaries with higher utilization of primary care have lower CRC incidence and mortality and lower overall mortality. Increasing and promoting access to primary care in the United States for Medicare beneficiaries may help decrease the national burden of CRC. PRIMARY FUNDING SOURCE American Cancer Society.

Influence of Primary Care on Breast Cancer Outcomes Among Medicare Beneficiaries

PURPOSE We used the Surveillance Epidemiology and End Results (SEER)-Medicare database to explore the association between primary care and breast cancer outcomes. METHODS Using a retrospective cohort study of 105,105 female Medicare beneficiaries with a diagnosis of breast cancer in SEER registries during the years 1994–2005, we examined the total number of office visits to primary care physicians and non–primary care physicians in a 24-month period before cancer diagnosis. For women with invasive cancers, we examined the odds of diagnosis of late-stage disease, according to the American Joint Commission on Cancer (AJCC) (stages III and IV vs stages I and II), and survival (breast cancer specific and all cause) using logistic regression and proportional hazards models, respectively. We also explored whether including noninvasive cancers, such as ductal carcinoma in situ (DCIS), would alter results and whether prior mammography was a potential mediator of associations. RESULTS Primary care physician visits were associated with improved breast cancer outcomes, including greater use of mammography, reduced odds of late-stage diagnosis, and lower breast cancer and overall mortality. Prior mammography (and resultant earlier stage diagnosis) mediated these associations in part, but not completely. Similar results were seen for non–primary care physician visits. Results were similar when women with DCIS were included in the analysis. CONCLUSIONS Medicare beneficiaries with breast cancer had better outcomes if they made greater use of a primary care physician’s ambulatory services. These findings suggest adequate primary medical care may be an important factor in achieving optimal breast cancer outcomes.

A Genome-Wide Investigation of MicroRNA Expression Identifies Biologically-Meaningful MicroRNAs That Distinguish between High-Risk and Low-Risk Intraductal Papillary Mucinous Neoplasms of the Pancreas

Background Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNAs that accurately classify IPMN risk status. Methodology/Principal Findings In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P<10−3, area underneath the curve (AUC) = 87%). The same trend was observed in the validation phase (AUC = 74%). Low miR-99b expression was associated with main pancreatic duct involvement (P = 0.021), and serum albumin levels were positively correlated with miR-99a (r = 0.52, P = 0.004) and miR-100 expression (r = 0.49, P = 0.008). Literature, validated miRNA:target gene interactions, and pathway enrichment analysis supported the candidate miRNAs as tumor suppressors and regulators of PDAC development. Microarray analysis revealed that oncogenic targets of miR-130a (ATG2B, MEOX2), miR-342-3p (DNMT1), and miR-126 (IRS-1) were up-regulated in high- versus low-risk IPMNs (P<0.10). Conclusions This pilot study highlights miRNAs that may aid in preoperative risk stratification of IPMNs and provides novel insights into miRNA-mediated progression to pancreatic malignancy. The miRNAs identified here and in other recent investigations warrant evaluation in biofluids in a well-powered prospective cohort of individuals newly-diagnosed with IPMNs and other pancreatic cysts and those at increased genetic risk for these lesions.

The effects of primary care on breast cancer mortality and incidence among Medicare beneficiaries

Primary care physician (PCP) services may have an impact on breast cancer mortality and incidence, possibly through greater use of screening mammography.

Sentinel lymph node biopsy is indicated for patients with thick clinically lymph node-negative melanoma

Sentinel lymph node biopsy (SLNB) is indicated for the staging of clinically lymph node‐negative melanoma of intermediate thickness, but its use is controversial in patients with thick melanoma.

The Influence of Dermatologist and Primary Care Physician Visits on Melanoma Outcomes Among Medicare Beneficiaries

Background: Ambulatory visits to dermatologists and primary care physicians (PCPs) may improve melanoma outcomes through early detection. We sought to measure the effect of dermatologist and PCP visits on melanoma stage at diagnosis and mortality. Methods: We used data from the database linking Surveillance Epidemiology and End Results (SEER) and Medicare data (1994 to 2005) to examine patterns of dermatologist and PCP ambulatory visits before diagnosis for 18,884 Medicare beneficiaries with invasive melanoma or unknown stage at diagnosis. Visits were assessed during the 2-year time interval before the month of diagnosis. We examined whether dermatologist and PCP visits were associated with diagnosis of thinner melanomas (defined as local stage tumors having Breslow thickness <1 mm) and lower melanoma mortality. Results: Medicare beneficiaries visiting both a dermatologist and PCP before diagnosis had greater odds of diagnosis of a thin melanoma (adjusted odds ratio, 1.26; 95% confidence interval, 1.12–1.41) and lower melanoma mortality (adjusted hazard ratio 0.66, 95% confidence interval, 0.57–0.76) compared with those without such visits. The mortality findings were attenuated once stage at diagnosis was adjusted for in the multivariable model. Conclusion: Improved melanoma outcomes among Medicare beneficiaries may depend on adequate access and use of dermatologist and PCP services.