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Research BackgroundCurrently, multiple myeloma is the second most common hematological malignancy in the U.S., constituting 1% of all cancers. With conventional treatment, the median survival time is typically 3–4 years, although it can be extended to 5–7 years or longer with advanced treatments. Recent research indicated that an increase in osteoclast (OC) activity is often associated withmultiple myeloma (MM) and that a decrease inosteoblast (OB) activity contributesto the osteolytic lesions in MM. Normally, the populations of OCs and OBs are inequilibrium, and an imbalance in this statecontributes to the development of lesions.Research proceduresA multi-scale agent-based multiple myeloma model was developed to simulate the proliferation, migration and death of OBs and OCs. Subsequently, this model was employed to investigate the efficacy of thethree most commonly used drugs for MM treatment under the following two premises: the reduction in the progression of MM and the re-establishment of the equilibrium between OCs and OBs.Research purposesThe simulated results not only demonstrated the capacity of the model to choose optimal combinations of the drugs but also showed that the optimal use of the three drugs can restore the balance between OCs and OBs as well as kill MMs. Furthermore, the drug synergism analysis function of the model revealed that restoring the balance between OBs and OCs can significantly increase the efficacy of drugs against tumor cells.

RAB28 is a farnesylated, ciliary G‐protein. Patient variants in RAB28 are causative of autosomal recessive cone‐rod dystrophy (CRD), an inherited human blindness. In rodent and zebrafish models, the absence of Rab28 results in diminished dawn, photoreceptor, outer segment phagocytosis (OSP). Here, we demonstrate that Rab28 is also required for dusk peaks of OSP, but not for basal OSP levels. This study further elucidated the molecular mechanisms by which Rab28 controls OSP and inherited blindness. Proteomic profiling identified factors whose expression in the eye or whose expression at dawn and dusk peaks of OSP is dysregulated by loss of Rab28. Notably, transgenic overexpression of Rab28, solely in zebrafish cones, rescues the OSP defect in rab28 KO fish, suggesting rab28 gene replacement in cone photoreceptors is sufficient to regulate Rab28‐OSP. Rab28 loss also perturbs function of the visual cycle as retinoid levels of 11‐cRAL, 11cRP, and atRP are significantly reduced in larval and adult rab28 KO retinae (p < .05). These data give further understanding on the molecular mechanisms of RAB28‐associated CRD, highlighting roles of Rab28 in both peaks of OSP, in vitamin A metabolism and in retinoid recycling.

Many pragmatic clustering methods have been developed to group data vectors or objects into clusters so that the objects in one cluster are very similar and objects in different clusters are distinct based on some similarity measure. The availability of time course data has motivated researchers to develop methods, such as mixture and mixed-effects modelling approaches, that incorporate the temporal information contained in the shape of the trajectory of the data. However, there is still a need for the development of time-course clustering methods that can adequately deal with inhomogeneous clusters (some clusters are quite large and others are quite small). Here we propose two such methods, hierarchical clustering (IHC) and iterative pairwise-correlation clustering (IPC). We evaluate and compare the proposed methods to the Markov Cluster Algorithm (MCL) and the generalised mixed-effects model (GMM) using simulation studies and an application to a time course gene expression data set from a study containing human subjects who were challenged by a live influenza virus. We identify four types of temporal gene response modules to influenza infection in humans, i.e., single-gene modules (SGM), small-size modules (SSM), medium-size modules (MSM) and large-size modules (LSM). The LSM contain genes that perform various fundamental biological functions that are consistent across subjects. The SSM and SGM contain genes that perform either different or similar biological functions that have complex temporal responses to the virus and are unique to each subject. We show that the temporal response of the genes in the LSM have either simple patterns with a single peak or trough a consequence of the transient stimuli sustained or state-transitioning patterns pertaining to developmental cues and that these modules can differentiate the severity of disease outcomes. Additionally, the size of gene response modules follows a power-law distribution with a consistent exponent across all subjects, which reveals the presence of universality in the underlying biological principles that generated these modules.