Patient perspective on decisions to switch disease-modifying treatments in relapsing-remitting multiple sclerosis.

BACKGROUND: There are now large cohorts of people with relapsing-remitting multiple sclerosis (pwRRMS) who have taken several Disease-Modifying Treatments (DMTs). Studies about switching DMTs mostly focus on clinical outcomes rather than patients' decision-making. Neurologists are now required to support decisions at various times during the relapsing disease course and they do so with concerns about DMTs risks. This qualitative study investigates how pwRRMS weigh up the pros and cons of DMTs, focusing on perceptions of effectiveness and risks when new treatments are considered. OBJECTIVE: To increase understanding of people's experiences of decision-making when switching DMTs. METHODS: 30 semi-structured interviews were conducted with pwRRMS in England. 16 participants had switched DMT and their experiences were compared with those who had only taken one DMT. Interviews were analysed thematically to answer: what main factors influence people's decision-making to switch DMTs and why? RESULTS: Of the 16 participants with experience of switching DMT, eight had taken two or more DMTs; eight had taken three or more. Two was the DMT median. This study demonstrated that despite the term "switching" implying that similar treatments are inter-changeable, for pwRRMS taking new treatments involves different emotions, routines, risks, prognosis and communication experiences. Two meta themes identified were: 1) A distinctive, rapid and emotional decision-making process where old emotions related to MS prognosis are revisited. 2) Switching has a different impact on communication for escalation or de-escalation processes. CONCLUSION: Switching DMT involves different routines, risks, prognosis and communication experiences. These decisions are emotionally difficult because of the fear about transitioning to secondary progressive MS, and DMT effectiveness uncertainty. Patient centred decision aids should include information about first and consecutive treatment decisions.

Mitoxantrone in relapsing-remitting and rapidly progressive multiple sclerosis: Ten-year clinical outcomes post-treatment with mitoxantrone.

BACKGROUND: Mitoxantrone (MTX) has been used as an effective disease modifying treatment (DMT) in multiple sclerosis (MS). Evidence from studies demonstrates benefits of reduced relapse rates, MRI disease activity and disability progression in patients treated with MTX. While effective, MTX use has been limited due to potential adverse effects (AE) ranging from mild to potentially life-threatening AEs such as cardiotoxicity, bone marrow suppression and hematological malignancies. In this study we aimed to review the long-term clinical efficacy, tolerability, and AE profile of treatment with MTX in patients both with relapsing-remitting and rapidly progressive MS over a 10-year follow-up period. METHODS: We collected prospective data of 70 patients with relapsing-remitting and rapidly progressive MS treated with MTX and followed-up over a 10-year period. Expanded disability status scale (EDSS) scores and annualized relapse rates (ARR) were assessed 1 year prior to MTX treatment, and at different time points (1, 2, 3, 5 and 10 years) during follow-up. We recorded the time to first relapse and 0.5-point EDSS increase to assess efficacy. We also obtained frequency data on AEs and patients withdrawn from treatment. RESULTS: 70 patients were started on treatment with MTX with 53 patients (34 relapsing-remitting MS, 19 progressive disease) completing the course. Mean EDSS progressed from 5.5 to 6.5 in the relapsing-remitting group and 6.7 to 9.0 in the progressive group over the study period. ARR in the RRMS group reduced at all time points from 2.2 prior to MTX to 0.3 by year 10. We reported 3 significant AEs, one chicken pox and subsequent acute promyelocytic leukemia, one left ventricular systolic dysfunction, one pancytopenia. The commonest AE reported was nausea/vomiting in 28 (40%) patients. Seventeen patients (5 relapsing-remitting, 12 progressive disease) stopped treatment. In fifteen (87%) of these this was due to lack of efficacy. In the remaining 2 patients, MTX was stopped due to one patient developing chicken pox and the other developing first-degree heart block. CONCLUSION: Our study demonstrated that MTX is an effective disease modifying treatment for relapsing-remitting MS with a well-established risk profile. While MTX is now used less frequently, many MS and neurology services continue to follow-up patients who have been treated with MTX previously. Therefore, understanding the long-term effects risks and benefits remains relevant in this patient group. MTX is also a low-cost treatment in comparison to other high efficacy MS disease-modifying treatments and this may be beneficial in low resource settings.

Two Sides of the Same Coin: The Role of Developmental pathways and pluripotency factors in normal mammary stem cells and breast cancer metastasis.

Breast cancer initiation and progression are often observed as the result of dysregulation of normal developmental processes and pathways. Studies focused on normal mammary stem/progenitor cell activity have led to an understanding of how breast cancer cells acquire stemness-associated properties including tumor initiation, survival and multi-lineage differentiation into heterogeneous tumors that become difficult to target therapeutically. Importantly, more recent investigations have provided valuable insight into how key developmental regulators can impact multiple phases of metastasis, where they are repurposed to not only promote metastatic phenotypes such as migration, invasion and EMT at the primary site, but also to regulate the survival, initiation and maintenance of metastatic lesions at secondary organs. Herein, we discuss findings that have led to a better understanding of how embryonic and pluripotency factors contribute not only to normal mammary development, but also to metastatic progression. We further examine the therapeutic potential of targeting these developmental pathways, and discuss how a better understanding of compensatory mechanisms, crosstalk between pathways, and novel experimental models could provide critical insight into how we might exploit embryonic and pluripotency regulators to inhibit tumor progression and metastasis.

Use of coping strategies in multiple sclerosis: Association with demographic and disease-related characteristics✰.

BACKGROUND: Coping positively and negatively influences psychosocial and other outcomes in multiple sclerosis (MS), but there is conflicting evidence about the use of different coping strategies and their associations with demographic and disease characteristics. Our aims were to examine which coping strategies are used by a large sample of people with MS, then to identify any associations between demographic and disease related factors with use of individual coping strategies. METHODS: Participants in the Trajectories of Outcomes in Neurological Conditions (TONiC) study completed the Coping Orientations to Problems Experienced (COPE60) questionnaire. Relationships between demographic and clinical characteristics and coping strategies were examined by multiple ordinal logistic regression to assess the effect of each potential predictor after adjustment for other possible covariates. RESULTS: From 722 patients, the most commonly used strategy was Acceptance, followed by Active Coping, Planning and Positive Reinterpretation and Growth. All but two strategies showed significant associations with demographic and clinical characteristics. The most marked effects were found for Restraint, with people in employment 2.1 times as likely to utilise this strategy compared to those unemployed, and Seeking of Emotional Social Support and Focus on and Venting of Emotions, which were utilised twice as much by women compared to men. Behavioural and Mental Disengagement were highly associated with greater disability and not being in employment. CONCLUSION: Clinicians should be aware of several disease and demographic characteristics that are associated with use of potentially maladaptive coping strategies.

The miR-106b-25 cluster mediates breast tumor initiation through activation of NOTCH1 via direct repression of NEDD4L.

Tumor-initiating cells (TIC) represent a subset of tumor cells with increased self-renewal capability. TICs display resistance to frontline cancer treatment and retain the ability to repopulate a tumor after therapy, leading to cancer relapse. NOTCH signaling has been identified as an important driver of the TIC population, yet mechanisms governing regulation of this pathway in cancer remain to be fully elucidated. Here we identify a novel mechanism of NOTCH regulation and TIC induction in breast cancer via the miR-106b-25 miRNA cluster. We show that the miR-106b-25 cluster upregulates NOTCH1 in multiple breast cancer cell lines, representing both estrogen receptor (ER+) and triple negative breast cancer (TNBC) through direct repression of the E3 ubiquitin ligase, NEDD4L. We further show that upregulation of NOTCH1 is necessary for TIC induction downstream of miR-106b-25 in both ER + and TNBC breast cancer cells, and that re-expression of NEDD4L is sufficient to reverse miR106b-25-mediated NOTCH1 upregulation and TIC induction. Importantly, we demonstrate a significant positive correlation between miR-106b-25 and NOTCH1 protein, yet a significant inverse correlation between miR-106b-25 and NEDD4L mRNA in human breast cancer, suggesting a critical role for the miR106b-25/NEDD4L/NOTCH1 axis in the disease. Further, we show for the first time that NEDD4L expression alone is significantly associated with a better relapse-free prognosis for breast cancer patients. These data expand our knowledge of the mechanisms underlying NOTCH activation and TIC induction in breast cancer, and may provide new avenues for the development of therapies targeting this resistant subset of tumor cells.

On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL-based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance, and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL-based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL DRs in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity.

The miR-106b-25 cluster targets Smad7, activates TGF-ß signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer.

The role of TGF-ß signaling in tumorigenesis is paradoxical: it can be tumor suppressive or tumor promotional, depending on context. The metastatic regulator, Six1, was recently shown to mediate this switch, providing a novel means to explain this elusive 'TGF-ß paradox'. Herein, we identify a mechanism by which Six1 activates the tumor promotional arm of TGF-ß signaling, via its ability to upregulate the miR-106b-25 microRNA cluster, and further identify a novel function for this cluster of microRNAs. Although expression of the miR-106b-25 cluster is known to overcome TGF-ß-mediated growth suppression via targeting p21 and BIM, we demonstrate for the first time that this same cluster can additionally target the inhibitory Smad7 protein, resulting in increased levels of the TGF-ß type I receptor and downstream activation of TGF-ß signaling. We further show that the miR-106b-25 cluster is sufficient to induce an epithelial-to-mesenchymal transition and a tumor initiating cell phenotype, and that it is required downstream of Six1 to induce these phenotypes. Finally, we demonstrate a significant correlation between miR-106b, Six1, and activated TGF-ß signaling in human breast cancers, and further show that high levels of miR-106b and miR-93 in breast tumors significantly predicts shortened time to relapse. These findings expand the spectrum of oncogenic functions of miR-106b-25, and may provide a novel molecular explanation, through the Six1 regulated miR-106b-25 cluster, by which TGF-ß signaling shifts from tumor suppressive to tumor promoting.

Eya2 is required to mediate the pro-metastatic functions of Six1 via the induction of TGF-ß signaling, epithelial-mesenchymal transition, and cancer stem cell properties.

Six1 is a critical regulator of embryonic development that requires interaction with the Eya family of proteins (Eya1-4) to activate the transcription of genes involved in neurogenesis, myogenesis and nephrogenesis. Although expression of Six1 and Eya family members is predominantly observed in development, their overexpression is observed in numerous cancers. Importantly, both Six1 and Eya have independently been shown to mediate breast cancer metastasis, but whether they functionally interact during tumor progression has not been explored. Herein, we demonstrate that knockdown of Eya2 in MCF7 mammary carcinoma cells reverses the ability of Six1 to induce transforming growth factor-ß signaling, as well as to induce characteristics associated with epithelial-mesenchymal transition and cancer stem cells, suggesting that Six1 is dependent on Eya2 to mediate numerous pro-metastatic characteristics. The importance of the Six1-Eya interaction in human breast cancer is underscored by the finding that high levels of Six1 correlate with shortened time to relapse and metastasis as well as decreased survival only when co-expressed with high levels of Eya2. Overall, these data implicate Eya2 as a necessary co-factor for many of the metastasis promoting functions of Six1, suggesting that targeting the Six1-Eya interaction may inhibit breast cancer progression. As Six1 and Eya2 are not highly expressed in most adult tissues, the Six1-Eya interaction may be a valuable future therapeutic target whose inhibition would be expected to impair breast cancer progression while conferring limited side effects.

Expression of Six1 homeobox gene during development of the mouse submandibular salivary gland.

BACKGROUND: Members of the Six family of homeoproteins are expressed in numerous tissues during vertebrate embryogenesis, and are critical regulators of both cell proliferation and survival. Here we report the temporal and spatial expression of Six1 during maturation of the mouse submandibular salivary gland (SSG) from embryonic day 18.5 (E18.5) to postnatal day 28. Additionally, we examine the role of Six1 during SSG development using Six1-deficient mice. METHODS: Six1 expression was assessed by reverse transcription-polymerase chain reaction, Western blot, and immunofluorescence. Proliferation was measured by bromodeoxyuridine (BrdU) incorporation index, and apoptosis was evaluated by TUNEL assay. RESULTS: Six1 mRNA and protein levels are high in the epithelial SSG cells at E18.5 and decrease progressively in the postnatal maturing SSG. Although SSGs from Six1(-/-) embryos are significantly smaller than wild type SSGs, the histological structures of the SSG acini and ducts are similar. Six1(-/-) salivary epithelial cells exhibit an intrinsic defect in cell proliferation accompanied by a significant reduction in the Six1 target gene cyclin A1, previously shown to be a critical mediator of Six1-induced proliferation. CONCLUSION: Our results suggest that the reduction in size of Six1(-/-) SSGs is result of a decrease in cell proliferation during development/maturation.

Multi-system complications of hypothermia: a case of recurrent episodic hypothermia with a review of the pathophysiology of hypothermia.

A 61-year-old woman with secondary progressive multiple sclerosis presented on six occasions over a 2-year period with severe hypothermia (31-33.5 degrees C). This resulted in numerous multi-system complications comprising acute pancreatitis, hepatitis, gastrointestinal haemorrhage, psychiatric disturbance, bradycardia, paradoxical sweating, thrombocytopenia, anaemia and raised inflammatory markers. Septic screens were consistently normal. On each occasion she was successfully treated with passive external rewarming and made a complete recovery. This is the first reported case of such extensive sequelae in a single patient with recurrent hypothermic episodes. This unusual patient provides an invaluable insight into the natural history and pathophysiology of hypothermia. The case report is followed by a review of dysfunctional thermoregulation and pathophysiology of hypothermia-induced multi-system complications. A key learning point is to recognise that the clinical manifestations of hypothermia may be widespread and serious but are nonetheless reversible. In addition, one should consider the differential diagnosis of covert hypothermia in those patients with episodic confusion, as hypothermia is under-recognised, particularly in older people, who are prone to accidental hypothermia, and in those with common neurological conditions, such as stroke, head injury and multiple sclerosis, that may have suboptimal thermoregulation.

Maintaining Psoroptes ovis (Acari: Psoroptidae) off-host in the laboratory.

Feeding and maintaining sheep scab mites off-host is an important step towards achieving a safer, environmentally-friendly means of controlling sheep scab disease. The test arena developed by Thind and Muggleton (Exp Appl Acarol 22:543-552, 1998) has been adapted for feeding and maintaining Psoroptes ovis off-host. The test arenas are simple to construct and use, and escape-proof to all stages of mites. The performance of the test arenas was assessed by determining the survival of the scab mites at 33 and 36 degrees C and >95% r.h. on different diets. With this test arena the best reported mean survival of 10.3 days was achieved with both females and nymphs at a temperature of 33 degrees C on a diet of sheep serum; the mean maximum survival of females at these conditions was 18.8 days, which is at least a threefold improvement on previous reports. With further development it may be possible to adapt the test arena for assessing both slow and fast acting agents for controlling sheep scab.

Cell cycle regulation of the human Six1 homeoprotein is mediated by APC(Cdh1).

The Six1 homeoprotein is an important mediator of normal development, where it is critical for the proliferation of precursor cell populations that ultimately constitute the muscle, kidney and inner ear, among other organs. Interestingly, its overexpression has been observed in numerous cancers, where it contributes to the proliferative and metastatic ability of the cancer cells. Here we show that Six1 not only regulates the cell cycle, but is itself regulated throughout the cell cycle via ubiquitin-mediated proteolysis. The protein is present from the G(1)/S boundary until mitosis, when it is degraded via the anaphase-promoting complex (APC) with its activating subunit Cdh1. However, unlike most identified APC(Cdh1) targets, Six1 does not contain functional destruction or KEN box motifs that are necessary for its degradation. Instead, the Six1 protein contains multiple, as yet undefined, sequences within its N- and C-termini responsible for its degradation, including an N-terminal region that binds to Cdh1. Cell cycle regulation of Six1 occurs both transcriptionally and post-translationally via phosphorylation; therefore, this study demonstrates a third and novel mechanism of cell cycle-specific regulation of Six1, underscoring the importance of confining its activity to a defined cell cycle window from the G(1)/S boundary to early mitosis.

Assessment of susceptibility of the poultry red mite Dermanyssus gallinae (Acari: Dermanyssidae) to some acaricides using an adapted filter paper based bioassay.

A previously described bioassay was modified to assess the response of the poultry red mite, an important ectoparasite of fowl, to a selected group of acaricides. The adapted bioassay is simple to use, escape-proof and provides data that can be subjected to probit analysis. The reproducibility of the method was assessed by three tests with alpha-cypermethrin against a reference strain, which produced dose-response lines that did not differ significantly (chi(2)=1.39, 2 d.f., p=0.50), and had a derived common slope of 1.89. In addition, a limited evaluation study enabled assessment of response to commercial formulations of bifenthrin, bifenthrin+malathion and cypermethrin by field populations of the poultry red mite.

Laboratory studies on the use of two new arenas to evaluate the impact of the predatory mites Blattisocius tarsalis and Cheyletus eruditus on residual populations of the stored product mite Acarus siro.

Residual populations of storage mites sheltering in crevices and cracks escape conventional control treatments and are implicated in the infestation of newly harvested grain. In a series of 24 h laboratory tests, the performance of solitary adults of two predatory mite species, Cheyletus eruditus (Schrank) and Blattisocius tarsalis (Berlese), were assessed for controlling small numbers of the flour mite Acarus siro (L.). Tests were carried out in the presence or absence of prey refuges or grain debris to afford shelter to the flour mites. While C. eruditus had a significant effect on the motile stages of A. siro, in contrast B. tarsalis had a significant effect on the eggs. The maximum percentage of motile stages of A. siro eaten by C. eruditus was 82%, whereas the minimum percentage of A. siro eggs eaten by B. tarsalis was 99%. While the performance of C. eruditus in predating on motile stages of the flour mite was hindered by the presence of the prey refuge (38% eaten) and grain debris (25% eaten), the performance of B. tarsalis in predating on flour mite eggs was unaffected (100% eaten in presence of prey refuge or grain debris). In prolonged exposures (36 days) the performance of 2, 4 or 8 adult predators, either a single species or a combination of both, was assessed for their ability to control a population of the flour mite developing up to F(2) from an initial inoculum of 80 females and 20 males, allowed to oviposit for 72 h in the absence of predatory mites. The maximum reduction in prey population of 80% was achieved with eight B. tarsalis. Combining the two predatory species did not enhance the reduction of A. siro population.

A simple pump-assisted method for collecting live, undamaged Psoroptes ovis from sheep using circulating saline.

The availability of large numbers of undamaged sheep scab mites, Psoroptes ovis, would be beneficial for discovery screening and development trials. There are several reported procedures for removing scab mites from sheep but they have limitations. To overcome this, a simple but versatile method employing the use of pumped saline was developed to remove all stages of the P. ovis mite from sheep. The method takes no more than 2 min to remove mites from the selected site with relative ease and is not affected by the condition of the fleece or lesion. The number of mites removed with the new method was 5-10 times more than detected by visual examination. These mites were undamaged and survived off-host for up to 16 days. The robust, portable equipment is easy to use under field conditions, making this method suitable for use as a diagnostic tool for early detection and monitoring of scab mites thus providing opportunities for development of novel alternative control strategies.

Multiple sclerosis and pregnancy.

Multiple sclerosis causes disability in young adults and, like most autoimmune diseases, affects women more commonly than men. The disease can therefore present at a time when many have, or are considering, starting a family. The effect of pregnancy on the outcome of multiple sclerosis is reviewed and the management of pregnant women who have multiple sclerosis is discussed.

Expression of cyclins E1 and E2 during mouse development and in neoplasia.

Cyclin E1 (formerly called cyclin E) and the recently described cyclin E2 belong to the family of E-type cyclins that operate during the G(1)/S phase progression in mammalian cells. The two E-cyclins share a catalytic partner, cyclin-dependent kinase 2 (CDK2), and activate their associated kinase activities at similar times during cell cycle progression. Despite these similarities, it is unknown whether the two proteins perform distinct functions, or, alternatively, they control S-phase entry of different cell types in a tissue-specific fashion. To start addressing in vivo functions of E-cyclins, we determined the expression pattern of cyclins E1 and E2 during normal mouse development. We found that the two E-cyclins showed very similar patterns of expression; both were expressed within the proliferating compartment during embryo development. Analyses of cells and tissues lacking members of the retinoblastoma (pRB) family of proteins revealed that the expression of both cyclins is controlled in a pRB-dependent, but p107- and p130-independent fashion, likely through the pRB-dependent E2F transcription factors. We also found that cyclins E1 and E2 are expressed at high levels in mouse breast tumors driven by the Myc oncogene. Last, we found that cyclin E2 is overexpressed in approximately 24% of analyzed human mammary carcinomas. Collectively these findings suggest that the expression of cyclins E1 and E2 is governed by similar molecular circuitry.

Health status and quality of life of people with multiple sclerosis.

PURPOSE: The aim of this study was to ascertain the health status and quality of life of a community based cohort of people with multiple sclerosis. METHOD: A postal questionnaire with self-completed measures of impairment, disability, physical dependency and quality of life was sent to a random sample of 203 people with multiple sclerosis from a population register. The sample was stratified according to five disease courses. The population register is of the prevalent population of 760 people with multiple sclerosis resident in the Leeds Health Authority. The register used multiple sources of ascertainment and is prospectively maintained with new incident cases. RESULTS: The estimated mean age of people with multiple sclerosis is 46 years (SE: 0.85), and mean duration of disease is 14.4 years (SE: 0.69). Almost four in five (78 %) are female, and one in six (17%) live alone. Impairments of balance, vision and memory are common and in all cases there is little difference in the frequency between disease course groups. In contrast, impairments of bladder and bowel are more common in those with a progressive disease course. Disability is more common in those with a progressive disease course but all scores on the SF36 Physical Function scale are low and demonstrate the disabling consequences of the disease, irrespective of disease course. These consequences must contribute to the fact that over two-thirds (68 %) were not employed at the time of the survey. Quality of life does not differ across disease course groups, but rather varies by age and duration. CONCLUSIONS: People with multiple sclerosis experience a range of impairments and disabilities. Those with progressive disease courses experience greater levels of impairment and disability than other groups. There is not a straightforward exchange between health status and quality of life. A measure of subjective quality of life may reflect adjustment to disease, such that, for example, the longer the duration, the older the individual, the more likely the person will report a relatively good quality of life.

Developing a disease-specific quality of life measure for people with multiple sclerosis.

OBJECTIVES: To develop a patient-completed disease-specific measure of quality of life in multiple sclerosis and to validate the measure in a community-based population of people with multiple sclerosis. METHODS: The items in the scale were selected in focus group sessions of people with multiple sclerosis. The initial scale included 25 items and was tested in subgroups of 150 people from a population register of people with multiple sclerosis in Leeds. Following further developmental phases, a restructured 16-item scale was tested on a random sample of 200 people with multiple sclerosis from the population register, stratified according to disease course. This led to a final eight-item unidimensional scale, the Leeds Multiple Sclerosis Quality of Life (LMSQoL) scale. RESULTS: After initial development a 16-item scale was found to be both reliable and valid. Cronbach's alpha for the 16-item scale was 0.86. The test-retest correlation was 0.74, using a two-week retest interval. However, convergent validity with the General Well Being Index was 0.67 and with the SF-36 Physical Function Scale was 0.68. This suggested that the scale straddled these two concepts and was confirmed by fit of the data to the Rasch measurement model. This revealed the potential for a reduced eight-item version of the scale. The eight-item scale had a closer association to well-being (0.83) than to physical function (0.39), had good internal consistency (0.79) and test-retest reliability (0.85). There were virtually no floor or ceiling effects for the scale. CONCLUSIONS: The study presents a disease-specific measure of quality of life in multiple sclerosis, the Leeds Multiple Sclerosis Quality of Life (LMSQoL) scale. The instrument is brief, easy to use and practical to administer in clinic or as a postal questionnaire. It measures a construct related to well-being, and provides an important adjunct to the measurement of outcome in multiple sclerosis.