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.

Mutations in LRRK2, encoding the multifunctional protein leucine-rich repeat kinase 2 (LRRK2), are a common cause of Parkinson disease. LRRK2 has been suggested to influence the cytoskeleton as LRRK2 mutants reduce neurite outgrowth and cause an accumulation of hyperphosphorylated Tau. This might cause alterations in the dynamic instability of microtubules suggested to contribute to the pathogenesis of Parkinson disease. Here, we describe a direct interaction between LRRK2 and β-tubulin. This interaction is conferred by the LRRK2 Roc domain and is disrupted by the familial R1441G mutation and artificial Roc domain mutations that mimic autophosphorylation. LRRK2 selectively interacts with three β-tubulin isoforms: TUBB, TUBB4, and TUBB6, one of which (TUBB4) is mutated in the movement disorder dystonia type 4 (DYT4). Binding specificity is determined by lysine 362 and alanine 364 of β-tubulin. Molecular modeling was used to map the interaction surface to the luminal face of microtubule protofibrils in close proximity to the lysine 40 acetylation site in α-tubulin. This location is predicted to be poorly accessible within mature stabilized microtubules, but exposed in dynamic microtubule populations. Consistent with this finding, endogenous LRRK2 displays a preferential localization to dynamic microtubules within growth cones, rather than adjacent axonal microtubule bundles. This interaction is functionally relevant to microtubule dynamics, as mouse embryonic fibroblasts derived from LRRK2 knock-out mice display increased microtubule acetylation. Taken together, our data shed light on the nature of the LRRK2-tubulin interaction, and indicate that alterations in microtubule stability caused by changes in LRRK2 might contribute to the pathogenesis of Parkinson disease.

J. Neurochem. (2011) 116, 304–315. Abstract Mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene are the most prevalent known cause of autosomal dominant Parkinson’s disease. The LRRK2 gene encodes a Roco protein featuring a Ras of complex proteins (ROC) GTPase and a kinase domain linked by the C‐terminal of ROC (COR) domain. Here, we explored the effects of the Y1699C pathogenic LRRK2 mutation in the COR domain on GTPase activity and interactions within the catalytic core of LRRK2. We observed a decrease in GTPase activity for LRRK2 Y1699C comparable to the decrease observed for the R1441C pathogenic mutant and the T1348N dysfunctional mutant. To study the underlying mechanism, we explored the dimerization in the catalytic core of LRRK2. ROC‐COR dimerization was significantly weakened by the Y1699C or R1441C/G mutation. Using a competition assay, we demonstrated that the intra‐molecular ROC : COR interaction is favoured over ROC : ROC dimerization. Interestingly, the intra‐molecular ROC : COR interaction was strengthened by the Y1699C mutation. This is supported by a 3D homology model of the ROC‐COR tandem of LRRK2, showing that Y1699 is positioned at the intra‐molecular ROC : COR interface. In conclusion, our data provides mechanistic insight into the mode of action of the Y1699C LRRK2 mutant: the Y1699C substitution, situated at the intra‐molecular ROC : COR interface, strengthens the intra‐molecular ROC : COR interaction, thereby locally weakening the dimerization of LRRK2 at the ROC‐COR tandem domain resulting in decreased GTPase activity.

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.

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.

Previous epidemiological studies had provided evidence for a link between the microbial dysbiosis and cancer, particularly colorectal cancer (CRC), yet the molecular basis of this link remains elusive. Recently, the association between plasma levels of trimethylamine-N-oxide (TMAO), an oxidised form of trimethylamine (TMA), and risks of various cancers was demonstrated. The discovery could potentially provide an alternative explanation for the aforementioned link, as TMA production is attributed to intestinal bacteria. Current evidence suggests that inflammation could be a potential molecular mechanism to explain the link between TMAO and cancer, although other mechanisms such as oxidative stress, DNA damage and disruption in protein folding might also play a role. This mini-review article first provides an overview of the current evidence for the association between TMAO and certain cancer types, and the potential mechanisms that could explain their association. Thereafter, the direction of further research on the connection between the intestinal microbiota, TMAO and cancer is suggested.