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Genome instability is a hallmark of cancer cells and can be accelerated by defects in cellular responses to DNA damage. This feature of malignant cells opens new avenues for tumor targeted therapy. MRE11-RAD50-NBS1 complex plays a crucial role in sensing and repair of DNA damage. Through interacting with other important players of DNA damage response, MRE11-RAD50-NBS1 complex is engaged in various DNA damage repair pathways. Mutations in any member of this complex may lead to hypersensitivity to genotoxic agents and predisposition to malignancy. It is assumed that the defects in the complex may contribute to tumorigenesis and that treatments targeting the defect may be beneficial to cancer patients. Here, we summarized the recent research findings of the role of MRE11-RAD50-NBS1 complex in tumorigenesis, cancer treatment and discussed the potential approaches of targeting this complex to treat cancer.

Non-muscle myosin IIA (NMIIA) protein plays an important role in cell cytokinesis and cell migration. The role and underlying regulatory mechanisms of NMIIA in pancreatic cancer (PC) remain elusive. We found that NMIIA is highly expressed in PC tissues and contributes to PC poor progression by using open microarray datasets from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and PC tissue arrays. NMIIA regulates β-catenin mediated EMT to promote the proliferation, migration, invasion, and sphere formation of PC cells in vitro and in vivo. NMIIA controls the β-catenin transcriptional activity by interacting with β-catenin. Moreover, MEK/ERK signaling is critical in MLC2 (Ser19) phosphorylation, which can mediate NMIIA activity and regulate Wnt/β-catenin signaling. These findings highlight the significance of NMIIA in tumor regression and implicate NMIIA as a promising candidate for PC treatment.

The mechanical properties of epithelial to mesenchymal transition (EMT) and a pancreatic cancer subpopulation with stem cell properties have been increasingly recognized as potent modulators of the effective of therapy. In particular, pancreatic cancer stem cells (PCSCs) are functionally important during tumor relapse and therapy resistance. In this review we have surveyed recent advances in the role of EMT and PCSCs in tumor progression, metastasis and treatment resistance, and the mechanisms of integrated with biochemical signals and the underlying pathways involved in treatment resistance of pancreatic cancer. These findings highlight the importance of confirming stem-cells markers and complex molecular signaling pathways controlling EMT and cancer stem cells in pancreatic cancer during tumor formation, progression, and response to therapy.

Control processes allow us to constrain the retrieval of semantic information from long-term memory so that it is appropriate for the task or context. Control demands are influenced by the strength of the target information itself and by the circumstances in which it is retrieved, with more control needed when relatively weak aspects of knowledge are required and after the sustained retrieval of related concepts. To investigate the neurocognitive basis of individual differences in these aspects of semantic control, we used resting-state fMRI to characterise the intrinsic connectivity of left ventrolateral prefrontal cortex (VLPFC), implicated in controlled retrieval, and examined associations on a paced serial semantic task, in which participants were asked to detect category members amongst distractors. This task manipulated both the strength of target associations and the requirement to sustain retrieval within a narrow semantic category over time. We found that individuals with stronger connectivity between VLPFC and medial prefrontal cortex within the default mode network (DMN) showed better retrieval of strong associations (which are thought to be recalled more automatically). Stronger connectivity between the same VLPFC seed and another DMN region in medial parietal cortex was associated with larger declines in retrieval over the course of the category. In contrast, participants with stronger connectivity between VLPFC and cognitive control regions within the ventral attention network (VAN) had better controlled retrieval of weak associations and were better able to sustain their comprehension throughout the category. These effects overlapped in left insular cortex within the VAN, indicating that a common pattern of connectivity is associated with different aspects of controlled semantic retrieval induced by both the structure of long-term knowledge and the sustained retrieval of related information.

While reading, our mind can wander to unrelated autobiographical information, creating a perceptually decoupled state detrimental to narrative comprehension. To understand how this mind-wandering state emerges, we asked whether retrieving autobiographical content necessitates functional disengagement from visual input. In Experiment 1, brain activity was recorded using functional magnetic resonance imaging (fMRI) in an experimental situation mimicking naturally occurring mind-wandering, allowing us to precisely delineate neural regions involved in memory and reading. Individuals read expository texts and ignored personally relevant autobiographical memories, as well as the opposite situation. Medial regions of the default mode network (DMN) were recruited during memory retrieval. In contrast, left temporal and lateral prefrontal regions of the DMN, as well as ventral visual cortex, were recruited when reading for comprehension. Experiment two used functional connectivity both at rest and during tasks to establish that (i) DMN regions linked to memory are more functionally decoupled from regions of ventral visual cortex than regions in the same network engaged when reading; and (ii) individuals with more self-generated mental contents and poorer comprehension, while reading in the lab, showed more decoupling between visually connected DMN sites important for reading and primary visual cortex. A similar pattern of connectivity was found in Experiment 1, with greater coupling between this DMN site and visual cortex when participants reported greater focus on reading in the face of conflict from autobiographical memory cues; moreover, the retrieval of personally relevant memories increased the decoupling of these sites. These converging data suggest we lose track of the narrative when our minds wander because generating autobiographical mental content relies on cortical regions within the DMN which are functionally decoupled from ventral visual regions engaged during reading. As your eyes scan these words, you may be thinking about what to make for dinner, how to address an unexpected hurdle at work, or how many emails are sitting, unread, in your inbox. This type of mind-wandering disrupts our focus and limits how much information we comprehend, whilst also being conducive to creative thinking and problem-solving. Despite being an everyday occurrence, exactly how our mind wanders remains elusive. One possible explanation is that the brain disengages from visual information from the external world and turns its attention inwards. A greater understanding of which neural circuits are involved in this process could reveal insights about focus, attention, and reading comprehension. Here, Zhang et al. investigated whether the brain becomes disengaged from visual input when our mind wanders while reading. Recalling personal events was used as a proxy for mind-wandering. Brain activity was recorded as participants were shown written statements; sometimes these were preceded by cues to personal memories. People were asked to focus on reading the statements or they were instructed to concentrate on their memories while ignoring the text. The analyses showed that recalling memories and reading stimulated distinct parts of the brain, which were in direct competition during mind-wandering. Further work examined how these regions were functionally connected. In individuals who remained focused on reading despite memory cues, the areas activated by reading showed strong links to the visual cortex. Conversely, these reading-related areas became ‘decoupled’ from visual processing centres in people who were focusing more on their internal thoughts. These results shed light on why we lose track of what we are reading when our mind wanders: recalling personal memories activates certain brain areas which are functionally decoupled from the regions involved in processing external information – such as the words on a page. In summary, the work by Zhang et al. builds a mechanistic understanding of mind-wandering, a natural feature of our daily brain activity. These insights may help to inform future interventions in education to improve reading, comprehension and focus.

Semantic retrieval is flexible, allowing us to focus on subsets of features and associations that are relevant to the current task or context: for example, we use taxonomic relations to locate items in the supermarket (carrots are a vegetable), but thematic associations to decide which tools we need when cooking (carrot goes with peeler). We used fMRI to investigate the neural basis of this form of semantic flexibility; in particular, we asked how retrieval unfolds differently when participants have advanced knowledge of the type of link to retrieve between concepts (taxonomic or thematic). Participants performed a semantic relatedness judgement task: on half the trials, they were cued to search for a taxonomic or thematic link, while on the remaining trials, they judged relatedness without knowing which type of semantic relationship would be relevant. Left inferior frontal gyrus showed greater activation when participants knew the trial type in advance. An overlapping region showed a stronger response when the semantic relationship between the items was weaker, suggesting this structure supports both top-down and bottom-up forms of semantic control. Multivariate pattern analysis further revealed that the neural response in left inferior frontal gyrus reflects goal information related to different conceptual relationships. Top-down control specifically modulated the response in visual cortex: when the goal was unknown, there was greater deactivation to the first word, and greater activation to the second word. We conclude that top-down control of semantic retrieval is primarily achieved through the gating of task-relevant ‘spoke’ regions.

Cognitive neuroscience has gained insight into covert states using experience sampling. Traditionally, this approach has focused on off-task states. However, task-relevant states are also maintained via covert processes. Our study examined whether experience sampling can also provide insights into covert goal-relevant states that support task performance. To address this question, we developed a neural state space, using dimensions of brain function variation, that allows neural correlates of overt and covert states to be examined in a common analytic space. We use this to describe brain activity during task performance, its relation to covert states identified via experience sampling, and links between individual variation in overt and covert states and task performance. Our study established deliberate task focus was linked to faster target detection, and brain states underlying this experience—and target detection—were associated with activity patterns emphasizing the fronto-parietal network. In contrast, brain states underlying off-task experiences—and vigilance periods—were linked to activity patterns emphasizing the default mode network. Our study shows experience sampling can not only describe covert states that are unrelated to the task at hand, but can also be used to highlight the role fronto-parietal regions play in the maintenance of covert task-relevant states.

Objective The clivus is trapezoidal in shape with uneven bone structure, the optimal number and position of screws for clival fixation are not clear. Therefore, this study aims to explore the optimization clival screw fixation method for occipitocervical instability using finite element analysis. Methods Seven finite element models were developed to evaluate biomechanical properties of clival screw fixation for treating occipitocervical stability, including (i) one clival screw fixation A1 and A2 models; (ii) two clival screws fixation B1 and B2 models; (iii) three clival screws fixation C1 and C2 models; (iv) four clival screws fixation D1 model. Loads of 1.5 Nm were applied to the model fRoM different directions to induce flexion, extension, lateral bending, and axial rotation movements. Results The regular triangle C1 type three clival screws fixation exhibited great stability, with RoM of 4.20° in flexion, 5.80° in extension, 0.85° in lateral bending, and 1.60° in axial rotation. The peak stress on the internal fixation devices were relatively low, with maximum screw stress of 194 MPa in flexion, 276 MPa in extension, 180 MPa in lateral bending, and 213 MPa in axial rotation; the maximum plate stress were 126, 554, 426, and 378 MPa, respectively. The areas with higher stress were mainly concentrated at the robust neck section of the plate. Conclusion The triangular configuration of three clival screws fixation represented the optimized anterior occipitocervical fixation method through the clivus, offering superior biomechanical stability, lower stress on the devices and dispersed stress distribution in the occipitocervical region. The clival screws fixation can achieve strong biomechanical stability in the occipitocervical region, which may serve as an optimized occipitocervical fixation method through the clivus.

TIGAR is an important factor associated with tumor glucose metabolism, but its function and underlying mechanism in human lung cancer remains unclear. Here, we analyzed the expression changes, prognosis, genetic alteration, related gene networks and metabolic pathways of TIGAR in lung cancer. The findings revealed that TIAGR level was augmented in LUAD and LUSC in comparison to the normal lung tissue. In addition, high TIAGR level was related to poorer outcome of patients with LUAD. Different alterations in TIGAR gene at various sites were observed in both LUAD and LUSC. The GO/KEGG analyses indicated that TIGAR affects the occurrence and progress of lung cancer through multiple metabolic pathways. Further, we established lung cancer cell models with TIGAR knockdown or overexpression to explore its effects on glucose metabolism, apoptosis and chemosensitivity. Our results indicated that TIGAR markedly inhibited glucose metabolism, ROS production, and susceptibility of lung cancer cells to cisplatin. Together, TIGAR plays a cancer-promoting role in lung cancer, which becomes a promising prognostic and therapeutic biomarker.

Objective Ni-Ti memory alloys are unusual materials for hard-tissue replacement because of their unique superelasticity, good biocompatibility, high strength, low specific gravity, low magnetism, wear resistance, corrosion resistance and fatigue resistance. The current study aims to evaluate its mechanical properties and provide biomechanical basis for the clinical application of the prosthesis. Methods Ten adult metacarpophalangeal joint specimens were randomly divided into a prosthesis group (n = 5, underwent metacarpophalangeal joint prosthesis) and a control group (n = 5, underwent sham operation). Firstly, the axial compression strength was tested with BOSE material testing machine to evaluate its biomechanical strength. Secondly, these specimens were tested for strain changes using BOSE material testing machine and GOM non-contact optical strain measurement system to evaluate the stress changes. Thirdly, fatigue test was performed between groups. Lastly, the mechanical wear of the metacarpophalangeal joint prosthesis was tested with ETK5510 material testing machine to study its mechanical properties. Results Axial compression stiffness in the prosthesis group was greater than that in the control group in terms of 30 ° and 60 ° flexion positions (P < 0.05). There was no statistically significant difference between two groups with regards to axial compression stiffness and stress change test (P > 0.05). In the fatigue wear test, the mean mass loss in the prosthesis group’s prosthesis was 17.2 mg and 17.619 mm 3 , respectively. The mean volume wear rate was 0.12%. There was no statistically significant difference in the maximum pull-out force of the metacarpal, phalangeal, and polymer polyethylene pads between the prosthesis group and the control group specimens. Conclusions Ni-Ti memory alloy metacarpophalangeal joint prosthesis conforms to the biomechanical characteristics of metacarpophalangeal joints without implants, and the fatigue strength can fully meet the needs of metacarpophalangeal joint activities after joint replacement.