Mutations in PARK8, encoding LRRK2, are the most common known cause of Parkinson's disease. The LRRK2 Roc-COR tandem domain exhibits GTPase activity controlling LRRK2 kinase activity via an ...intramolecular process. We report the interaction of LRRK2 with the dishevelled family of phosphoproteins (DVL1-3), key regulators of Wnt (Wingless/Int) signalling pathways important for axon guidance, synapse formation and neuronal maintenance. Interestingly, DVLs can interact with and mediate the activation of small GTPases with structural similarity to the LRRK2 Roc domain. The LRRK2 Roc-COR domain and the DVL1 DEP domain were necessary and sufficient for LRRK2–DVL1 interaction. Co-expression of DVL1 increased LRRK2 steady-state protein levels, an effect that was dependent on the DEP domain. Strikingly, LRRK2–DVL1-3 interactions were disrupted by the familial PARK8 mutation Y1699C, whereas pathogenic mutations at residues R1441 and R1728 strengthened LRRK2–DVL1 interactions. Co-expression of DVL1 with LRRK2 in mammalian cells resulted in the redistribution of LRRK2 to typical cytoplasmic DVL1 aggregates in HEK293 and SH-SY5Y cells and co-localization in neurites and growth cones of differentiated dopaminergic SH-SY5Y cells. This is the first report of the modulation of a key LRRK2-accessory protein interaction by PARK8 Roc-COR domain mutations segregating with Parkinson's disease. Since the DVL1 DEP domain is known to be involved in the regulation of small GTPases, we propose that: (i) DVLs may influence LRRK2 GTPase activity, and (ii) Roc-COR domain mutations modulating LRRK2–DVL interactions indirectly influence kinase activity. Our findings also link LRRK2 to Wnt signalling pathways, suggesting novel pathogenic mechanisms and new targets for genetic analysis in Parkinson's disease.
Breast cancer is the most common cancer type among women worldwide. With breast cancer patients and survivors being reported to experience a repertoire of symptoms that are detrimental to their ...quality of life, the development of breast cancer treatment strategies that are effective with minimal side effects is therefore required. Personalized medicine, the treatment process that is tailored to the individual needs of each patient, is recently gaining increasing attention for its prospect in the development of effective cancer treatment regimens. Indeed, recent studies have identified a number of genes and molecules that may be used as biomarkers for predicting drug response and severity of common cancer-associated symptoms. These would provide useful clues not only for the determination of the optimal drug choice/dosage to be used in personalized treatment, but also for the identification of gene or molecular targets for the development of novel symptom management strategies, which ultimately would lead to the development of more personalized therapies for effective cancer treatment. In this article, recent studies that would provide potential new options for personalized therapies for breast cancer patients and survivors are reviewed. We suggest novel strategies, including the optimization of drug choice/dosage and the identification of genetic changes that are associated with cancer symptom occurrence and severity, which may help in enhancing the effectiveness and acceptability of the currently available cancer therapies.
Purpose
To review recent pharmacogenomics studies on breast cancer patients undergoing tamoxifen therapy, highlighting how our knowledge on cytochrome P450 2D6 (CYP2D6) can help to guide the ...development of adjuvant therapies for these patients.
Methods
A comprehensive literature search was conducted. Articles reporting findings pertaining to the effect of CYP2D6 on the therapeutic efficacy of tamoxifen, those reporting how targeting CYP2D6 could inform tamoxifen-based therapy development, and those on the tamoxifen effects on cell lines and animal models were included in the review.
Results
With CYP2D6 being the primary enzyme for tamoxifen metabolism, single-nucleotide polymorphisms (SNPs) in this gene were one of the determinants in the rate of tamoxifen metabolism, thereby potentially having an effect on the efficacy of tamoxifen-based therapies. Our review indicates the potential effectiveness of targeting these SNPs, including those for the CYP2D6*10 allele (c. 100C > T), in modifying the level of tamoxifen metabolism. These findings suggest the importance of pharmacogenomics research in our understanding of the efficacy of adjuvant therapies. However, the involvement of multiple enzymes in tamoxifen metabolism, dietary factors, ethnic differences in gene frequencies, and patients’ compliance to tamoxifen therapies in studies do present challenges in pharmacogenomics research.
Conclusions
Pharmacogenomics could play important roles in mediating the advancement of tamoxifen-based adjuvant therapies. Research efforts should be directed towards the exploration of further SNPs of CYP2D6 that affect tamoxifen metabolism, as well as epigenetic changes in CYP2D6, enabling the design of precision medicine and confirming clinical validity in the use of pharmacogenomics for tamoxifen.
Adjuvant endocrine therapies are known to induce undesirable adverse effects such as vasomotor, vaginal and musculoskeletal symptoms among breast cancer patients. Drugs used in these therapies are ...often metabolised by cytochrome P450 (CYP) enzymes, in which their metabolising activities can be modified by single nucleotide polymorphisms (SNP) in CYP genes and CYP genotypes. This review aims to explore whether SNPs or genotypes of CYP are associated with the occurrence, frequency and severity of vasomotor, vaginal and musculoskeletal symptoms in breast cancer patients on adjuvant endocrine therapies.
A literature review was conducted using five electronic databases, resulting in the inclusion of 14 eligible studies, and their findings were presented narratively. Selected items from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist were used for critical appraisal of the reporting quality of the included studies.
Most of the included studies showed that SNPs or genotypes of CYP that modify its metabolising activity have no effect on the occurrence, frequency or severity of vasomotor symptoms, including hot flashes. One study showed no correlation of these genetic variations in CYP with musculoskeletal symptoms, and no data were available on the association between such genetic variations and vaginal symptoms.
Overall, genetic variations in CYP have no effect on the experience of hot flashes among breast cancer patients. We recommend exploration of the link between the active metabolites of chemotherapeutic drugs and the molecules shown to affect the occurrence or severity of hot flashes, and the establishment of the relationship between such genetic variations and patients' experience of musculoskeletal and vaginal symptoms. Subgroup analyses based on patients' duration of adjuvant endocrine therapies in such studies are recommended.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Individuals with intellectual disabilities (ID) may require assistance in accessing healthcare services, including cancer screening. A better understanding of the factors affecting cancer screening ...utilisation among these individuals is needed for the development of strategies to promote screening uptake in them. This review aimed to explore the facilitators of and barriers to cancer screening utilisation among people with ID. A literature search was conducted using five databases, and an additional snowball search yielded 16 studies for inclusion in the review. Overall, the methodological quality of these studies was good (43–100%). In this review, we noted barriers to screening among individuals with ID, including perceptions of fear, distress, and embarrassment; unpreparedness for screening; negative interactions with healthcare professionals; a lack of knowledge about cancer screening; mobility issues; a high severity of ID; and a lack of ability to provide consent and communicate verbally. Facilitators to screening among these individuals were also identified, including living in a supervised setting, prior use of other healthcare services, being educated about screening via social media, having carers accompany them to screening appointments, and having dual insurance coverage or a higher income. Our review highlights the current needs of individuals with ID undergoing cancer screening. Strategies should be developed to address these needs, such as the provision of training to healthcare professionals on how to conduct screening for people with ID.
•People with intellectual disability face multiple barriers to cancer screening.•Physicians should be trained to conduct cancer screening for these individuals.•Cancer screening provision should be augmented based on their unmet needs.
Breast cancer patients often experience symptoms that adversely affect their quality of life. It is understood that many of these symptoms tend to cluster together: while they might have different ...manifestations and occur during different phases of the disease trajectory, the symptoms often have a common aetiology that is a potential target for intervention. Understanding the symptom clusters associated with breast cancer might usefully inform the development of effective care plans for affected patients. The aim of this paper is to provide an updated systematic review of the known symptom clusters among breast cancer patients during and/or after cancer treatment. A search was conducted using five databases for studies reporting symptom clusters among breast cancer patients. The search yielded 32 studies for inclusion. The findings suggest that fatigue‐sleep disturbance and psychological symptom cluster (including anxiety, depression, nervousness, irritability, sadness, worry) are the most commonly‐reported symptom clusters among breast cancer patients. Further, the composition of symptom clusters tends to change across various stages of cancer treatment. While this review identified some commonalities, the different methodologies used to identify symptom clusters resulted in inconsistencies in symptom cluster identification. It would be useful if future studies could separately examine the symptom clusters that occur in breast cancer patients undergoing a particular treatment type, and use standardised instruments across studies to assess symptoms. The review concludes that further studies could usefully determine the biological pathways associated with various symptom clusters, which would inform the development of effective and efficient symptom management strategies.
This study assessed the knowledge, attitudes and practices (KAP) towards coronavirus disease 2019 (COVID-19) among South Asians in Hong Kong and examined the factors that affect KAP towards COVID-19 ...in this population. This cross-sectional descriptive study recruited participants with assistance from South Asian community centres and organisations. A total of 352 participants completed questionnaires to assess their level of KAP towards COVID-19. The mean knowledge score was 5.38/10, indicating a relatively low knowledge level. The participants expressed certain misconceptions regarding the prevention of COVID-19 infection. They perceived a mild risk related to the disease, had positive attitudes regarding its prevention and often implemented recommended disease-preventive measures, such as maintaining social distance (88.1%) and wearing masks in public (94.3%). Participants who were male, had a secondary school education or lower and who perceived a lower risk of being infected and lower self-efficacy were less likely to implement preventive measures. Culturally and linguistically appropriate health education could be developed to increase the knowledge of South Asians, especially those with lower education levels, about COVID-19 and to encourage them to implement the necessary preventive measures.
Cancer patients often experience severe financial distress due to the high cost of their treatment, and strategies are needed to objectively measure this financial distress. The COmprehensive Score ...for financial Toxicity-Functional Assessment of Chronic Illness Therapy (COST-FACIT) is one instrument used to measure such financial distress. This study aimed to translate the COST-FACIT (Version 2) COST-FACIT-v2 instrument into traditional Chinese (COST-FACIT-v2 TC) and evaluate its psychometric properties.
The Functional Assessment of Chronic Illness Therapy (FACIT) translation method was adopted. The translated version was reviewed by an expert panel and by 20 cancer patients for content validity and face validity, respectively, and 640 cancer patients, recruited from three oncology departments, completed the translated scale. Its reliability was evaluated in terms of internal consistency and test-retest reliability. Confirmatory factor analysis has been used to evaluate the one- and two-factor structures of the instrument reported in the literature. The convergent validity was examined by the correlation with health-related quality of life (HRQoL) and psychological distress. Known-group validity was examined by the difference in the COST-FACIT-v2 (TC) total mean score between groups with different income levels and frequency of health care service use.
The COST-FACIT-v2 (TC) showed good content and face validity and demonstrated high internal consistency (Cronbach's alpha, 0.86) and acceptable test-retest reliability (intraclass correlation coefficient, 0.71). Confirmatory factor analysis showed that the one- and two-factor structures of the instrument that have been reported in the literature could not be satisfactorily fitted to the data. Psychological distress correlated significantly with the COST-FACIT-v2 (TC) score (r = 0.47; p < 0.001). HRQOL showed a weak to moderate negative correlation with the COST-FACIT-v2 (TC) score (r = - 0.23 to - 0.46; p < 0.001). Significant differences were seen among the COST-FACIT-v2 (TC) scores obtained in groups of different income level and frequency of health care service use.
The COST-FACIT-v2 (TC) showed some desirable psychometric properties to support its validity and reliability for assessing cancer patients' level of financial toxicity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Regular physical activity has been demonstrated to contribute to physical and psychological health. Nevertheless, pregnant women generally exhibit low levels of physical activity. Implementation of ...interventions that enhance the self-efficacy of pregnant women on increasing physical activity is required. This paper provides an in-depth review of studies reporting the effect of various physical activity interventions dedicated for pregnant women on pregnancy-related issues, including gestational weight gain, pain and depression, physical activity level, and quality of life among these individuals. Five databases were used in searching the literature. Findings of the included studies were presented narratively, and appraisal of their methodological quality was conducted using the quality assessment tool developed by Effective Public Health Practice Project. Review findings demonstrated that physical activity interventions are effective in enhancing physical activity levels of pregnant women. Further, they are potentially useful in alleviating pregnancy-related pain and psychological symptoms, reducing gestational weight gain, and increasing self-efficacy in enhancing physical activity levels among these individuals. Nevertheless, inconsistencies in findings between studies hamper the drawing of firm conclusions on these latter outcomes. Overall, studies demonstrated a positive effect of physical activity interventions on the well-being and physical and psychological health of pregnant women.
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