The experiences of people with disability and their families/carers navigating the NDIS planning process in regional, rural and remote regions of Australia: Scoping review.

BACKGROUND: Australia's National Disability Insurance Scheme (NDIS) was launched in 2013 to provide financial support packages for people with disability to purchase supports and services to enhance independence. People with disability are required to develop a plan with the National Disability Insurance Agency (NDIA), the government department responsible for managing the NDIS. This scoping review aims to ascertain the level of research into people's experience of the NDIS planning process in these geographic areas. METHODOLOGY: Research publication databases were searched using a specific search string to identify research about people with disability and their families/carer's experiences of the NDIS planning process in regional, rural and remote regions of Australia. The Mixed Methods Appraisal Tool (MMAT) was adopted to appraise the quality of the research publications. Research publications focused on Aboriginal and Torres Strait Islander people were additionally appraised using the Aboriginal and Torres Strait Islander Quality Appraisal Tool developed by the Centre for Excellence in Aboriginal Chronic Disease Knowledge Translation and Exchange. A thematic synthesis of the publications' contents was undertaken to ascertain people with disabilities and carers experience of the NDIS planning process. RESULTS: Ten (N = 10) research papers were found that met the inclusion criteria. Two papers were policy reviews and reported on the improvements of the NDIS planning process since its conception. The analysis found the research archive focused on five themes: (1) healthcare workforce and NDIA staff; (2) NDIS package holders and carers lack of awareness of the NDIS; (3) cultural/socio-economic barriers; (4) travel funding; and (5) emotional burden of the NDIS planning process. CONCLUSION: There are limited papers available that explore people's experiences of the NDIS planning process in regional, rural and remote regions of Australia. This systematic review illuminates the difficulties, barriers and concerns of people with disability and their carers about the planning process.

Disability workforce and the NDIS planning process in regional, rural and remote regions of Australia: Scoping review.

BACKGROUND: The Australian geographically rural and remote disability workforce has historically demonstrated difficulties to keep up with the demand for quality services and supports for people with disability. In 2013, the National Disability Insurance Scheme (NDIS) was launched to provide individualised disability support packages to meet people's needs. To receive funding, people with disability are required to develop a NDIS plan. That plan is then funded by the National Disability Insurance Agency (NDIA), the government agency responsible for managing the NDIS. Although the NDIS has been operating for almost 10 years, there is limited research into the planning experiences of the workforce in regional, rural and remote regions of Australia. This review aims to ascertain the level of scholarly investigation into workers' experiences of NDIS planning. METHODOLOGY: Research publication databases were searched using a specific search string to identify publications that included reference to the workforce's experiences of the NDIS planning process in regional, rural and remote regions of Australia. The Mixed Methods Appraisal Tool (MMAT) was adopted to appraise the quality of the research publications. Research publications that focused on those working with Aboriginal and Torres Strait Islander people were also appraised using the Aboriginal and Torres Strait Islander Quality Appraisal Tool developed by the Centre for Excellence in Aboriginal Chronic Disease Knowledge Translation and Exchange. A thematic synthesis of the publications was undertaken to ascertain disability and health workforce experiences of the NDIS planning process. RESULTS: Seven papers met the selection criteria. Two papers were policy reviews and reported the improvements of the NDIS planning process since its inception. These studies reported four reoccurring themes: (1) cultural/socioeconomic and geographical factors; (2) administrative burden and bureaucracy; (3) values, culture and geography; and (4) burden on allied health workers. CONCLUSION: The NDIS planning process has developed and progressed since its rollout in 2013. There are limited research papers available that describe the workforce's experience of the planning process in regional, rural and remote regions. More research in this area is needed to identify the experiences of the disability workforce in relation to the NDIS planning process.

Responding to the 'thin' markets of rural and remote disability services. Quantitative and spatial analysis is part of the picture.

Policymakers, funding bodies and service provider agencies require objective indicators to ensure quality, equity and access. We sought to depict the availability of rural and remote allied health and disability services in Queensland using one such indicator (spatial analysis) to explore concepts related to 'thin' markets, including market sufficiency and market diversity. Our findings suggested, counter-intuitively, that more remote settings had greater disability service sufficiency and diversity than larger regional centres. While on careful interpretation this face-value observation can be rationalised, it can also be used to influence decision making to the detriment of remote area consumers and communities. Most importantly, it does not adequately incorporate consumer, community and service provider realities in remote areas. This led us to consider additional factors that should routinely be acknowledged to broaden planning for disability services in rural and remote settings. We suggest a number of additional considerations that should also inform policy, funding and service planning decisions. The challenge facing all stakeholders is to develop new indicators that are meaningfully reflective of the realities of rural and remote consumers, families, communities and service providers, as well as market realities.

Immunohistochemical evaluation of immune cell infiltration in canine gliomas.

Evasion of the immune response is an integral part of the pathogenesis of glioma. In humans, important mechanisms of immune evasion include recruitment of regulatory T cells (Tregs) and polarization of macrophages toward an M2 phenotype. Canine glioma has a robust immune cell infiltrate that has not been extensively characterized. The purpose of this study was to determine the distribution of immune cells infiltrating spontaneous intracranial canine gliomas. Seventy-three formalin-fixed, paraffin-embedded tumor samples were evaluated using immunohistochemistry for CD3, forkhead box 3 (FOXP3), CD20, Iba1, calprotectin (Mac387), CD163, and indoleamine 2,3-dioxygenase (IDO). Immune cell infiltration was present in all tumors. Low-grade and high-grade gliomas significantly differed in the numbers of FoxP3+ cells, Mac387+ cells, and CD163+ cells (P = .006, .01, and .01, respectively). Considering all tumors, there was a significant increase in tumor area fraction of CD163 compared to Mac387 (P < .0001), and this ratio was greater in high-grade tumors than in low-grade tumors (P = .005). These data warrant further exploration into the roles of macrophage repolarization or Treg interference therapy in canine glioma.

Previously Diagnosed Reticulum Cell Hyperplasia in Decalcified Rat Bone Marrow Stain Positive for Ionized Calcium Binding Adapter Molecule 1 (Iba1): A Monocytic/Macrophage Cell Marker.

Reticulum cell hyperplasia (RCH) was a term used for many years by the National Toxicology Program (NTP) to describe a certain non-neoplastic bone marrow lesion of rats. Retrospective microscopic evaluation of RCH lesions and immunohistochemistry analyses were performed to reassess and further characterize these lesions. The NTP database was searched to identify femoral bone marrow specimens diagnosed with RCH from 1981 to 2014 (n = 254). The diagnosis last occurred in 2003, after which the term "cellular infiltration" was used. Eighty-three RCH slides, spanning 22 years, representing 34 different chemicals, were selected for microscopic review, and a subset (23) was chosen for ionized calcium binding adapter molecule 1 (Iba1) immunohistochemical staining; initial investigations revealed Iba1 worked as a macrophage marker on decalcified tissue. The following diagnoses were made upon reevaluation: 36 were consistent with cellularity increased, macrophage, 22 with histiocytic sarcoma, 8 with increased myeloid cells, 4 with autolysis, and 13 were normal appearance. All 23 RCH lesions stained positive for Iba1. Fifty-eight of 83 bone marrows previously diagnosed with RCH are consistent morphologically and immunohistochemically with cells of histiocytic origin. These results will help with interpretation of historical data and demonstrates that Iba1 can be used in decalcified bone marrow sections.

Do GISTs Occur in Rats and Mice? Immunohistochemical Characterization of Gastrointestinal Tumors Diagnosed as Smooth Muscle Tumors in The National Toxicology Program.

The majority of the tumors in the gastrointestinal (GI) tract of rats and mice, with spindle cell morphology, are diagnosed as smooth muscle tumors (SMTs). Similarly, several decades ago human GI tumors with spindle cell morphology were also diagnosed as SMTs. However, later investigations identified most of these tumors in humans as gastrointestinal stromal tumors (GISTs). The GISTs are considered to arise from the interstitial cells of Cajal located throughout the GI tract. Positive immunohistochemical staining with CKIT antibody is a well-accepted diagnostic marker for GISTs in humans. Since there is a considerable overlap between the histomorphology of SMTs and GISTs, it is not possible to distinguish them on hematoxylin and eosin stained sections. As a result, GISTs are not routinely diagnosed in toxicological studies. The current study was designed to evaluate the tumors diagnosed as leiomyoma or leiomyosarcoma in the National Toxicology Program's 2-year bioassays using CKIT, smooth muscle actin, and desmin immunohistochemistry. The results demonstrate that most of the mouse SMTs diagnosed as leiomyoma or leiomyosarcoma are likely GISTs, whereas in rats the tumors are likely SMTs and not GISTs.

Immunohistochemistry in Investigative and Toxicologic Pathology.

Immunohistochemistry (IHC) is a valuable tool in pathology. This review provides a brief description of the technical aspects of IHC and a detailed discussion on the variables that affect the results, interpretation, and reproducibility of IHC results. Lists of antibodies that have and have not worked in IHC on various mouse and rat tissues in our laboratory are provided as a guidance for selection of antibodies. An approach to IHC method optimization is presented. Finally, the critical information that should be included as a part of peer-reviewed manuscript is also discussed.

Preparation of Three-dimensional (3-D) Human Liver (HepaRG) Cultures for Histochemical and Immunohistochemical Staining and Light Microscopic Evaluation.

The use of three-dimensional (3-D) in vitro culture systems (spheroids, organoids) in biomolecular and drug discovery research has become increasingly popular. The popularity is due, in part, to a diminished reliance on animal bioassays and a desire to develop physiologically relevant cell culture systems that simulate the in vivo tissue microenvironment. Most evaluations of 3-D cultures are by confocal microscopy and high-content imaging; however, these technologies do not allow for detailed cellular morphologic assessments or permit basic hematoxylin and eosin histologic evaluations. There are few studies that have reported detailed processes for preparing 3-D cultures for paraffin embedding and subsequent use for histochemical or immunohistochemical staining. In an attempt to do so, we have developed a protocol to paraffin-embed human liver spheroids that can be sectioned with a microtome and mounted onto glass slides for routine histochemical and immunohistochemical staining and light microscopic evaluations.

Open letter to Minister Helen Morton.

This letter was sent to the Honourable Helen Morton by Emma Campbell after the Occupational Therapy Australia National Conference. A number of members of First Australian and Australian OTs online were keen to show their support for Emma's letter and share this with other OT colleagues.

Fruit and Vegetable Intake, Food Security, Barriers to Healthy Eating, and Empowerment among Dietetic Interns and Physician Assistant Interns: A Cross-Sectional Pilot Study.

Students are required to complete supervised practice hours prior to becoming Registered Dietitians and Physician Assistants. Research suggests that environmental and social factors affect dietetic interns' diets during their internship, although these factors have not been studied among physician assistant interns. This cross-sectional study utilized an online survey to compare dietetic interns' (n = 81) and physician assistant interns' (n = 79) fruit and vegetable intake, food security, barriers to healthy eating, and empowerment for making healthy dietary choices during an internship. Differences were assessed via independent t-tests and chi-square distributions. The significance was set at p < 0.05. Dietetic interns had a higher vegetable intake (p = 0.002) while physician assistant interns had higher rates of food insecurity (p = 0.040). Dietetic interns reported a greater impact on their dietary choices due to mental fatigue (p = 0.006), while physician assistant interns' dietary choices were more heavily impacted by peer influence, interactions with patients, and interactions with preceptors (p < 0.05). There was not a group difference in overall empowerment (p = 0.157), although both groups rated empowerment for asking for help with food and nutrition challenges the lowest of the empowerment sub-items. Addressing interns' unique needs may support students' educational success and wellbeing once they are professionals, promote a diverse workforce, and ensure optimal care for patients.

Engineering of a synthetic electron conduit in living cells.

Engineering efficient, directional electronic communication between living and nonliving systems has the potential to combine the unique characteristics of both materials for advanced biotechnological applications. However, the cell membrane is designed by nature to be an insulator, restricting the flow of charged species; therefore, introducing a biocompatible pathway for transferring electrons across the membrane without disrupting the cell is a significant challenge. Here we describe a genetic strategy to move intracellular electrons to an inorganic extracellular acceptor along a molecularly defined route. To do so, we reconstitute a portion of the extracellular electron transfer chain of Shewanella oneidensis MR-1 into the model microbe Escherichia coli. This engineered E. coli can reduce metal ions and solid metal oxides ∼8× and ∼4× faster than its parental strain. We also find that metal oxide reduction is more efficient when the extracellular electron acceptor has nanoscale dimensions. This work demonstrates that a genetic cassette can create a conduit for electronic communication from living cells to inorganic materials, and it highlights the importance of matching the size scale of the protein donors to inorganic acceptors.

Describing ovarian cycles, pregnancy characteristics, and the use of contraception in female white-faced marmosets, Callithrix geoffroyi.

Endocrine data and characteristics of nonconceptive ovarian cycling and pregnancy are limited within the genus Callithrix to the common marmoset (C. jacchus) and Wied's black tufted-ear marmoset (C. kuhlii). This article presents patterns of urinary pregnanediol-3-glucuronide (PdG) excretion, as determined by enzyme immunoassay, throughout the course of ovarian cycling and pregnancy in white-faced marmosets (C. geoffroyi). Furthermore, characteristics of reproductive parameters including litter size, duration of gestation, maternal age, and information about ovarian cycling following administration of contraceptives are also described. A steep increase in PdG, an indication of ovulation, characterizes normative ovarian cycles, with peak-to-peak intervals between cycles being 27.82 ± 1.49 days in length. PdG excretion (µg/mg Cr) across pregnancy peaked during the 1st and 2nd trimesters (1st = 20.71 ± 2.98, 2nd = 21.16 ± 2.60) and declined gradually to near preconception levels over the 3rd trimester until parturition (3rd = 5.74 ± 1.60). Gestation lasted 148.55 ± 1.89 days. Most pregnancies (82.8%) resulted in an immediate postpartum ovulation (PPO) of 17.45 ± 2.22 days with 58.3% of PPOs resulting in conception. No differences in PdG excretion during the 1st trimester between full pregnancies and miscarriages were found, and pregnancy characteristics such as litter size, duration of gestation, and maternal age were not associated with PdG concentrations. Administration of cloprostenol resulted in shorter peak-to-peak cycle durations, but ovulation was detectable with similar concentrations of peak PdG to a normal nonconceptive cycle. Conversely, medroxyprogesterone acetate (DMPA) injections resulted in little to no PdG excretion across the ovarian cycle. Both methods of contraception providing effective prevention of conception. Overall, these results show that strong similarities in reproductive parameters persist within the genus Callithrix and to a lesser extent across the Callitrichidae family.

Inter-pathologist agreement on diagnosis, classification and grading of canine glioma.

Histopathological evaluation of tumours is a subjective process, but studies of inter-pathologist agreement are uncommon in veterinary medicine. The Comparative Brain Tumour Consortium (CBTC) recently published diagnostic criteria for canine gliomas. Our objective was to assess the degree of inter-pathologist agreement on intracranial canine gliomas, utilising the CBTC diagnostic criteria in a cohort of eighty-five samples from dogs with an archival diagnosis of intracranial glioma. Five pathologists independently reviewed H&E and immunohistochemistry sections and provided a diagnosis and grade. Percentage agreement and kappa statistics were calculated to measure inter-pathologist agreement between pairs and amongst the entire group. A consensus diagnosis of glioma subtype and grade was achieved for 71/85 (84%) cases. For these cases, percentage agreement on combined diagnosis (subtype and grade), subtype only and grade only were 66%, 80% and 82%, respectively. Kappa statistics for the same were 0.466, 0.542 and 0.516, respectively. Kappa statistics for oligodendroglioma, astrocytoma and undefined glioma were 0.585, 0.566 and 0.280 and were 0.516 for both low-grade and high-grade tumours. Kappa statistics amongst pairs of pathologists for combined diagnosis varied from 0.352 to 0.839. 8 % of archival oligodendrogliomas and 61% of archival astrocytomas were reclassified as another entity after review. Inter-pathologist agreement utilising CBTC guidelines for canine glioma was moderate overall but varied from fair to almost perfect between pairs of pathologists. Agreement was similar for oligodendrogliomas and astrocytomas but lower for undefined gliomas. These results are similar to pathologist agreement in human glioma studies and with other tumour entities in veterinary medicine.

Closing the gap: Supporting occupational therapists to partner effectively with First Australians.

BACKGROUND/AIM: Occupational therapists need to be able to work competently with all clients, including First Australians. Currently, there are no national standards for occupational therapists working with First Australian clients. This article presents current issues in practice and education with First Australians and makes recommendations for the future. METHODS: A survey of 41 occupational therapists working with, or interested in First Australian health issues was conducted at a workshop held at the Australian National Occupational Therapy Conference in 2008. Results of the workshop group discussions were also collated. RESULTS: Several themes emerged from both survey data and discussions. A substantial proportion of participants rated their confidence and competence to work with First Australians as low to moderate. Higher levels of perceived confidence and competence were associated with current experience in the field. Discussions centred around six major themes: building relationships, service provision and design, education and training of occupational therapists, increasing First Australian representation within occupational therapy, professional issues and political issues. These themes were further collapsed into areas of action, which could be taken by individuals, managers, researchers and professional bodies to improve practice with First Australians. CONCLUSIONS: Occupational therapists will benefit from coordinated efforts, on individual and systemic levels, to work more effectively, and in partnership with, First Australians. Such developments should include guidelines for practice, education and research; professional development and networking opportunities; and improved collaboration, especially with First Australian partners, on a national level.

Environmental and systemic challenges to delivering services for Aboriginal adults with a disability in Central Australia.

PURPOSE: This two-year (2016-2018) study aimed to identify what a good life is for Aboriginal people with disability in remote Central Australia and how service providers can support them to achieve a good life. This paper presents the findings that relate to barriers to delivering services for Aboriginal people with disability. METHODS: In-depth interviews and focus groups were held with Aboriginal people with disability and their carers aged at least 18 years from the Ngaanyatjarra Pitjantjatjara Yankunytjatjara (NPY) Lands and community organisations providing services there. The data were analysed using thematic analysis. RESULTS: There were 109 participants, of whom 47 were workers in service provider organisations and 62 were Aboriginal people. From the data, barriers to delivering services to support Aboriginal people to live a good life and solutions to overcome the barriers, were identified and described under the headings of environmental barriers and systemic issues. CONCLUSIONS: We discuss the policy implications of these findings with regard to addressing Indigenous disadvantage and how governments, service providers, communities, and Aboriginal people with disability and their families can work in partnership to address these barriers.Implications for RehabilitationIndigenous people with disability living in remote and very remote communities experience significant access and equity barriers to culturally responsive services that enable them to live a socially and culturally engaged life.Localised government and service provider disability policy approaches in Indigenous communities need to focus on both environmental and systemic issues.Greater investment in local remote communities is required to build the capacity of Indigenous families to support Aboriginal people with a disability to live a culturally and socially included life.

Function and distribution of circulating human PCSK9 expressed extrahepatically in transgenic mice.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is predominantly expressed in liver and regulates cholesterol metabolism by down regulating liver LDL receptor (LDLR) proteins. Here we report transgenic overexpression of human PCSK9 in kidney increased plasma levels of PCSK9 and subsequently led to a dramatic reduction in liver LDLR proteins. The regulation of LDLR by PCSK9 displayed tissue specificity, with liver being the most responsive tissue. Even though the PCSK9 transgene was highly expressed in kidney, LDLR proteins were suppressed to a lower extent in this tissue than in liver. Adrenal LDLR proteins were not regulated by elevated plasma PCSK9. hPCSK9 transgene expression and subsequent reduction of liver LDLR led to increases in plasma total cholesterol, LDL cholesterol, and ApoB, which were further increased by a high-fat, high-cholesterol diet. We also observed that the size distribution of hPCSK9 in transgenic mouse plasma was heterogeneous. In chow-fed mice, the majority of PCSK9 proteins were in free forms; however, feeding a high-fat, high-cholesterol diet resulted in a shift of hPCSK9 distribution toward larger complexes. PCSK9 distribution in human plasma also exhibited heterogeneity and individual variability in the percentage of PCSK9 in free form and in large complexes. We provide strong evidence to support that human PCSK9 proteins secreted from extrahepatic tissue are able to promote LDLR degradation in liver and increase plasma LDL. Our data also suggest that LDLR protein regulation by PCSK9 has tissue specificity, with liver being the most responsive tissue.

Improving membrane protein expression and function using genomic edits.

Expression of membrane proteins often leads to growth inhibition and perturbs central metabolism and this burden varies with the protein being overexpressed. There are also known strain backgrounds that allow greater expression of membrane proteins but that differ in efficacy across proteins. We hypothesized that for any membrane protein, it may be possible to identify a modified strain background where its expression can be accommodated with less burden. To directly test this hypothesis, we used a bar-coded transposon insertion library in tandem with cell sorting to assess genome-wide impact of gene deletions on membrane protein expression. The expression of five membrane proteins (CyoB, CydB, MdlB, YidC, and LepI) and one soluble protein (GST), each fused to GFP, was examined. We identified Escherichia coli mutants that demonstrated increased membrane protein expression relative to that in wild type. For two of the proteins (CyoB and CydB), we conducted functional assays to confirm that the increase in protein expression also led to phenotypic improvement in function. This study represents a systematic approach to broadly identify genetic loci that can be used to improve membrane protein expression, and our method can be used to improve expression of any protein that poses a cellular burden.

Role of art centres for Aboriginal Australians living with dementia in remote communities.

OBJECTIVE: To explore the role art centres in remote communities play for Aboriginal and Torres Strait Islander Australians living with dementia. METHODS: A comprehensive literature search was undertaken, with no restrictions on articles regarding year of publication. RESULTS: Art programmes have been found to be of benefit to both people living with dementia and their carers, particularly when programmes are administered in environments that are culturally revered. Findings indicate remote art centres play a key role in maintaining traditions, culture and practices unique to Aboriginal and Torres Strait Islanders, but there is a gap in knowledge regarding how they cater for the needs of people with dementia. CONCLUSION: Addressing this gap will be helpful in remote areas where prevalence of dementia is up to five times that of non-Aboriginal people, and there are limited health and support services. Further research is required to explore strengths and gaps of current practices.

Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfaces.

The pathogenesis of primary Sjogren's syndrome (SS), an autoimmune disease that targets the mucosa of exocrine tissues, is poorly understood. Although several mouse models have been developed that display features of SS, most of these are within the larger context of a lupus-like presentation. Immunity-related GTPase family M protein 1 (Irgm1) is an interferon-inducible cytoplasmic GTPase that is reported to regulate autophagy and mitochondrial homeostasis. Here, we report that naive Irgm1-/- mice display lymphocytic infiltration of multiple mucosal tissues including the lung in a manner reminiscent of SS, together with IgA class-predominant autoantibodies including anti-Ro and anti-La. This phenotype persists in the germ-free state, but is abolished by deletion of Irgm3. Irgm1-/- mice have increased local production in the lung of TECP15-idiotype IgA, a natural antibody with dual reactivity against host and pneumococcal phosphorylcholine. Associated with this, Irgm1-/- mice display enhanced opsonization and clearance of Streptococcus pneumoniae from the lung and increased survival from pneumococcal pneumonia. Taken together, our results identify Irgm1 as a master regulator of mucosal immunity that dually modulates evolutionarily conserved self- and other-directed immune responses at the interface of host with environment.

Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice.

In Drosophila and Caenorhabditis elegans, kinase suppressor of ras (KSR) positively modulates Ras/Raf-mitogen-activated protein kinase (MAPK) signaling. The precise signaling mechanism of mammalian KSR1 and its role in Ras-mediated transformation, however, remain uncertain. To gain insight into KSR1 function in vivo, we generated mice homozygous null for KSR1. ksr1-/- mice are viable and without major developmental defects. However, an unusual disorganized hair follicle phenotype manifest in epidermal growth factor receptor knockout mice is recapitulated in ksr1-/- mice, providing genetic support for the notion that epidermal growth factor receptor, Ras, and KSR1 are on the same signaling pathway in mammals. Furthermore, ksr1-/- mice allow for the definition of KSR1-dependent and -independent mechanisms of c-Raf-1 activation. In embryonic fibroblasts, epidermal growth factor and 12-O-tetradecanoylphorbol-13-acetate activated the MAPK cascade to a similar extent, yet only c-Raf-1 activation by epidermal growth factor depended on KSR1. Moreover, whereas the genesis of polyomavirus middle T antigen (MT)-driven mammary cancer appears independent of KSR1, KSR1 is obligate for v-Ha-ras-mediated skin tumor formation. The growth of MT-driven mammary tumor was moderately slowed in ksr1-/- mice, however, consistent with a decreased rate of proliferation of ksr1-/- cells (T cells and embryonic fibroblasts). Nonetheless, all ksr1-/- animals succumbed to mammary cancer. In contrast, papilloma formation in Tg.AC mice, resulting from skin-specific v-Ha-ras expression, was completely abrogated in the ksr1-/- background. Hence, MT-driven mammary tumor genesis, which is signaled through src and phosphatidylinositol 3'-kinase, appears KSR1 independent, whereas v-Ha-ras-mediated skin cancer, signaled through the Raf-1/MAPK cascade, requires KSR1. These results suggest KSR1 may represent a therapeutic target for Ras/MAPK signaling of human tumorigenesis.