Chemotherapy is a life-saving treatment for cancer patients, but also causes long-term cognitive impairment, or "chemobrain", in survivors. However, several challenges, including imprecise diagnosis criteria, multiple confounding factors, and unclear and heterogeneous molecular mechanisms, impede effective investigation of preventions and treatments for chemobrain. With the rapid increase in the number of cancer survivors, chemobrain is an urgent but unmet clinical need. Here, we leverage the extensive knowledge in various fields of neuroscience to gain insights into the mechanisms for chemobrain. We start by outlining why the post-mitotic adult brain is particularly vulnerable to chemotherapy. Next, through drawing comparisons with normal aging, Alzheimer's disease, and traumatic brain injury, we identify universal cellular mechanisms that may underlie the cognitive deficits in chemobrain. We further identify existing neurological drugs targeting these cellular mechanisms that can be repurposed as treatments for chemobrain, some of which were already shown to be effective in animal models. Finally, we briefly describe future steps to further advance our understanding of chemobrain and facilitate the development of effective preventions and treatments.Cognitive complaints are common among cancer patients during and after chemotherapy. Cross-sectional and longitudinal studies suggest that short-term memory, working memory, and verbal ability are most frequently affected, followed by visuospatial memory, executive functions, and attention span (for meta-analyses, see

Wolfram syndrome is a rare multisystem disease characterized by childhood-onset diabetes mellitus and progressive neurodegeneration. Most cases are attributed to pathogenic variants in a single gene, Wolfram syndrome 1 (WFS1). There currently is no disease-modifying treatment for Wolfram syndrome, as the molecular consequences of the loss of WFS1 remain elusive. Because diabetes mellitus is the first diagnosed symptom of Wolfram syndrome, we aimed to further examine the functions of WFS1 in pancreatic β cells in the context of hyperglycemia. Knockout (KO) of WFS1 in rat insulinoma (INS1) cells impaired calcium homeostasis and protein kinase B/Akt signaling and, subsequently, decreased cell viability and glucose-stimulated insulin secretion. Targeting calcium homeostasis with reexpression of WFS1, overexpression of WFS1’s interacting partner neuronal calcium sensor-1 (NCS1), or treatment with calpain inhibitor and ibudilast reversed deficits observed in WFS1-KO cells. Collectively, our findings provide insight into the disease mechanism of Wolfram syndrome and highlight new targets and drug candidates to facilitate the development of a treatment for this disorder and similar diseases.

Three types of commercially derived methylsilicone materials, Sylgard-184, Q(V)Q(H) (an MQ-based silicone containing no dimethylsiloxane, D units), and D(V)D(H) (a D-based silicone with no additives), were judiciously chosen to study the conditions under which long-lasting hydrophilicity after oxygen plasma treatment can be obtained. A 30 s plasma treatment time under controlled conditions was found to be optimal in terms of achieving the lowest initial advancing and receding contact angles of θ(A)/θ(R) = 10°/5° with undetectable surface damage. Vacuum treatment, a necessary step prior to plasma ignition that has been overlooked in previous studies, as well as room temperature curing were explored as means to remove low molecular weight species. For thin films (a few micrometers), 40 min vacuum treatment was sufficient to achieve low dynamic contact angles of θ(A)/θ(R) = 51-56°/38-43° on all three types of silicones measured more than 30 days after the plasma treatments. These values indicate superior hydrophilicity relative to what has been reported. The small and slow rise in contact angle over time is likely caused by the intrinsic nature of the silicone materials, i.e., surface reorientation of hydrophilic functional groups to the bulk and condensation of surface silanol groups, and is thus unavoidable. For thick films (∼1 mm), room temperature curing in addition to vacuum treatment was required to reduce hydrophobic recovery and to achieve long-lasting hydrophilicity. The final contact angles for thick samples were slightly higher than the corresponding thin film samples due to the greater "reservoir" depth and migration length for mobile species. In particular, Sylgard exhibited inferior performance among the thick samples, and we attribute this to the additives in its commercial formulation. Furthermore, unlike polydimethylsiloxane-based silicones, Q(V)Q(H) does not contain equilibration products of the Dn-type; its thin films perform as well as those of Sylgard and D(V)D(H). Silicones without D units are promising materials with intrinsically low hydrophobic recovery characteristics and long-lasting hydrophilicity after oxygen plasma treatment.

Adsorption of poly(vinyl alcohol) (PVOH), 99% and 88% hydrolyzed poly(vinyl acetate), to poly(dimethylsiloxane) (PDMS) substrates was studied. The substrates were prepared by covalently attaching linear PDMS polymers of 2, 9, 17, 49, and 116 kDa onto silicon wafers. As the PDMS molecular weight/thickness increases, the adsorbed PVOH thin films progressively transition from continuous to discontinuous morphologies, including honeycomb and fractal/droplet. The structures are the result of thin film dewetting that occurs upon exposure to air. The PVOH film thickness does not vary significantly on these PDMS substrates, implicating the PDMS thickness as the cause for the morphology differences. The adsorbed PVOH thin films are less stable and have a stronger tendency to dewet on thicker, more liquid-like PDMS layers. When PVOH(99%) and PVOH(88%) thin films are compared, fractal and droplet morphologies are observed on high molecular weight PDMS substrates, respectively. The formation of the unique fractal features in the PVOH(99%) thin films as well as other crystalline and semicrystalline thin films is most likely driven by crystallization during the dehydration process in a diffusion-limited aggregation fashion. The only significant enhancement in hydrophilicity via PVOH adsorption was obtained on PDMS(2k), which is completely covered with a PVOH thin film. To mimic the lower receding contact angle and less liquid-like character of the PDMS(2k) substrate, light plasma treatment of the higher molecular weight PDMS substrates was carried out. On the treated PDMS substrates, the adsorbed PVOH thin films are in the more continuous honeycomb morphology, giving rise to significantly enhanced wettability. Furthermore, hydrophobic recovery of the hydrophilized PDMS substrates was not observed during a 1 week period. Thus, light plasma oxidation and subsequent PVOH adsorption can be utilized as a means to effectively hydrophilize conventional PDMS substrates. This study illustrates that the stability and morphology of adsorbed polymer thin films depend on polymer crystallinity as well as substrate physical properties.

Background After chemotherapy, many cancer survivors suffer from long-lasting cognitive impairment, colloquially known as “chemobrain.” However, the trajectories of cognitive changes and the underlying mechanisms remain unclear. We previously established paclitaxel-induced inositol trisphosphate receptor (InsP3R)-dependent calcium oscillations as a mechanism for peripheral neuropathy, which was prevented by lithium pretreatment. Here, we investigated if a similar mechanism also underlay paclitaxel-induced chemobrain. Method Mice were injected with 4 doses of 20 mg/kg paclitaxel every other day to induced cognitive impairment. Memory acquisition was assessed with the displaced object recognition test. The morphology of neurons in the prefrontal cortex and the hippocampus was analyzed using Golgi-Cox staining, followed by Sholl analyses. Changes in protein expression were measured by Western blot. Results Mice receiving paclitaxel showed impaired short-term spatial memory acquisition both acutely 5 days post injection and chronically 23 days post injection. Dendritic length and complexity were reduced in the hippocampus and the prefrontal cortex after paclitaxel injection. Concurrently, the expression of protein kinase C α (PKCα), an effector in the InsP3R pathway, was increased. Treatment with lithium before or shortly after paclitaxel injection rescued the behavioral, cellular, and molecular deficits observed. Similarly, memory and morphological deficits could be rescued by pretreatment with chelerythrine, a PKC inhibitor. Conclusion We establish the InsP3R calcium pathway and impaired neuronal morphology as mechanisms for paclitaxel-induced cognitive impairment. Our findings suggest lithium and PKC inhibitors as candidate agents for preventing chemotherapy-induced cognitive impairment.