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PurposeTo assess atrophy differences among brain regions and time-dependent changes after whole-brain radiation therapy (WBRT).Materials and methodsTwenty patients with lung cancer who underwent both WBRT and chemotherapy (WBRT group) and 18 patients with lung cancer who underwent only chemotherapy (control group) were recruited. Three-dimensional T1WI were analyzed to calculate volume reduction ratio after WBRT in various brain structures. The volume reduction ratio of the hippocampus was compared among following 3 periods: 0–3, 4–7, and 8–11 months after WBRT.ResultsThe volume reduction ratio of the hippocampus was significantly higher in the WBRT group than in the control group (p < 0.05). In WBRT group, the volume reduction ratio of the hippocampus was significantly higher than that of the cortex and white matter (p < 0.05). There were significant differences in the volume reduction ratio between of 0–3 months and that of 4–7 months (p = 0.02) and between 4–7 months and that of 8–11 months (p = 0.01).ConclusionThe hippocampus is more vulnerable to the radiation compared with other brain regions and may become atrophic even in the early stage after WBRT.

PurposeThis study aims to investigate hippocampal subfield volumes in patients with hippocampal sclerosis (HS) without visually detectable MRI abnormalities and to determine the diagnostic accuracy using hippocampal subfield volumes.Materials and methodsWe examined 46 patients with unilateral HS who had a histopathological diagnosis, and 54 controls. The patients were divided into two groups; visually detectable HS (n = 26) and undetectable HS (n = 20) on MRI. The volumes of hippocampal subfield using FreeSurfer were compared among the three groups. Diagnostic accuracy was calculated as the AUC of ROC using cutoff values for each individual subfield.ResultsCompared with the controls, visually detectable HS showed significantly reduced volumes of all the hippocampal subfields and entire hippocampus, whereas visually undetectable HS showed significant atrophy only in the CA3 and hippocampus-amygdala-transition-area. To diagnose visually undetectable HS, the CA3 volumes had AUC of 0.719, which was higher than AUC of 0.614 based on the entire hippocampal volumes.ConclusionVisually undetectable HS demonstrated volume reductions in the CA3. Further, the CA3 volumes was more useful to diagnose visually undetectable HS compared with the entire hippocampal volumes.

In the cell cycle, the G1/S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6 dysregulates G1/S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G1 phase in cancer cell lines, including A549 human non–small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell‐death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell‐death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar‐type ATPase (V‐ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live‐cell imaging revealed that the abemaciclib‐induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes. We found that abemaciclib, a CDK4/6 inhibitor, exerted a potent cytocidal effect in cancer cell lines with an atypical cell death phenotype, which entailed formation of multiple cytoplasmic vacuoles, and both the formation of vacuoles and the induction of cell death were inhibited by V‐ATPase inhibitors. Precise live‐cell imaging and transmission electron microscopy revealed that these vacuoles were derived from lysosomes that expanded following acidification and contained undigested debris and remnants of organelles. Thus we here propose a unique form of cell death accompanied by swollen and dysfunctional lysosomes by abemaciclib treatment.

Optogenetics has become an indispensable tool for investigating brain functions. Although non-human primates are particularly useful models for understanding the functions and dysfunctions of the human brain, application of optogenetics to non-human primates is still limited. In the present study, we generate an effective adeno-associated viral vector serotype DJ to express channelrhodopsin-2 (ChR2) under the control of a strong ubiquitous CAG promoter and inject into the somatotopically identified forelimb region of the primary motor cortex in macaque monkeys. ChR2 is strongly expressed around the injection sites, and optogenetic intracortical microstimulation (oICMS) through a homemade optrode induces prominent cortical activity: Even single-pulse, short-duration oICMS evokes long-lasting repetitive firings of cortical neurons. In addition, oICMS elicits distinct forelimb movements and muscle activity, which are comparable to those elicited by conventional electrical ICMS. The present study removes obstacles to optogenetic manipulation of neuronal activity and behaviors in non-human primates. Non-human primates are useful models for understanding the human brain but application of optogenetics to non-human primates is challenging. The authors used optogenetic intracortical microstimulation in the primary motor cortex of macaques to elicit distinct forelimb movements and muscle activity.

SETBP1 is a potential epigenetic regulator whose hotspot mutations preventing proteasomal degradation are recurrently detected in myeloid malignancies with poor prognosis. It is believed that the mutant SETBP1 exerts amplified effects of wild-type SETBP1 rather than neomorphic functions. This indicates that dysregulated quantitative control of SETBP1 would result in the transformation of hematopoietic cells. However, little is known about the roles of endogenous SETBP1 in malignant and normal hematopoiesis. Thus, we integrated the analyses of primary AML and healthy samples, cancer cell lines, and a newly generated murine model, Vav1-iCre;Setbp1fl/fl. Despite the expression in long-term hematopoietic stem cells, SETBP1 depletion in normal hematopoiesis minimally alters self-renewal, differentiation, or reconstitution in vivo. Indeed, its loss does not profoundly alter transcription or chromatin accessibilities. Furthermore, although AML with high SETBP1 mRNA is associated with genetic and clinical characteristics for dismal outcomes, SETBP1 is dispensable for the development or maintenance of AML. Contrary to the evidence that SETBP1 mutations are restricted to myeloid malignancies, dependency on SETBP1 mRNA expression is not observed in AML. These unexpected results shed light on the unrecognized idea that a physiologically nonessential gene can act as an oncogene when the machinery of protein degradation is damaged.

ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis. BRD9 is a core non-canonical BAF component. Here the authors show that BRD9 plays a pivotal role in regulating the disease-related cell fate of hematopoietic stem cells. Its loss promotes myeloid skewing while impairing B cell development by altering CTCF-mediated chromatin states.

Cancer cells use autophagy for growth, survival, and cytoprotection from chemotherapy. Therefore, autophagy inhibitors appear to be good candidates for cancer treatment. Our group previously reported that macrolide antibiotics, especially azithromycin (AZM), have potent autophagy inhibitory effects, and combination treatment with tyrosine kinase inhibitors or proteasome inhibitors enhances their anti–cancer activity. In this study, we evaluated the effect of combination therapy with DNA‐damaging drugs and AZM in non–small‐cell lung cancer (NSCLC) cells. We found that the cytotoxic activities of DNA‐damaging drugs, such as doxorubicin (DOX), etoposide, and carboplatin, were enhanced in the presence of AZM in NSCLC cell lines, whereas AZM alone exhibited almost no cytotoxicity. This enhanced cell death was dependent on wild‐type‐p53 status and autophagosome‐forming ability because TP53 knockout (KO) and ATG5‐KO cells attenuated AZM‐enhanced cytotoxicity. DOX treatment upregulated lysosomal biogenesis by activating TFEB and led to lysosomal membrane damage as assessed by galectin 3 puncta assay and cytoplasmic leakage of lysosomal enzymes. In contrast, AZM treatment blocked autophagy, which resulted in the accumulation of lysosomes/autolysosomes. Thus, the effects of DOX and AZM were integrated into the marked increase in damaged lysosomes/autolysosomes, leading to prominent lysosomal membrane permeabilization (LMP) for apoptosis induction. Our data suggest that concomitant treatment with DNA‐damaging drugs and AZM is a promising strategy for NSCLC treatment via pronounced LMP induction. In this paper, we showed that coadministration of DNA‐damaging drugs and azithromycin (AZM), a macrolide antibiotic, enhanced cytotoxicity due to increased lysosomal membrane permeabilization (LMP). Because DNA‐damaging drugs induce LMP, cancer cells activate autophagy to remove damaged lysosomes by lysophagy. However, AZM inhibited lysophagy, as well as autophagy, resulting in the prominent cytoplasmic accumulation of damaged lysosomes for induction of LMP‐mediated apoptosis in non–small‐cell lung cancer cells.

The coronavirus disease 2019 (COVID-19) affects infected patients even after the acute phase and impairs their health and quality of life by causing a wide variety of symptoms, referred to as long COVID. Although the evidence is still insufficient, hypertension is suspected to be a potential risk factor for long COVID, and the occurrence of cardiovascular diseases seems to be a key facet of multiple conditions observed in long COVID. Nonetheless, there are few reports that comprehensively review the impacts of long COVID on hypertension and related disorders. As a sequel to our previous report in 2020 which reviewed the association of COVID-19 and hypertension, we summarize the possible influences of long COVID on hypertension-related organs, including the cardiovascular system, kidney, and endocrine system, as well as the pathophysiological mechanisms associated with the disorders in this review. Given that the clinical course of COVID-19 is highly affected by age and sex, we also review the impacts of these factors on long COVID. Lastly, we discuss areas of uncertainty and future directions, which may lead to better understanding and improved prognosis of clinical problems associated with COVID-19.

Inhibition of the renin-angiotensin system (RAS) has been shown to alleviate muscle atrophy both under pathological conditions and during physiological aging. We recently reported that the deletion of angiotensin converting enzyme 2 (ACE2), which converts Angiotensin II to Angiotensin-(1–7) in mice, leads to the early manifestation of aging-associated muscle weakness along with the increased expression of p16INK4a, a senescence-associated gene, and increased central nuclei in the tibialis anterior (TA) muscle in middle age. As ACE2 is multifunctional and functions beyond its role in the RAS, we investigated whether activation of the RAS primarily contributes to muscle weakness in ACE2 knockout (KO) mice by comparing these mice to Tsukuba hypertensive (TH) mice that overproduce human angiotensin II. The grip strength of young (6 months) and middle-aged (15 months) TH mice was consistently lower than that of wild-type mice at the same ages. Middle-aged TH mice were continuously lean with extremely reduced adiposity. Central nuclei in the gastrocnemius (GM) muscle were increased in ACE2KO mice, while no apparent morphological change was observed in the GM muscles of TH mice. Increased expression of p16INK4a along with alterations in the expression of several sarcopenia-associated genes were observed in the GM muscles of ACE2KO mice but not TH mice. These findings suggest that chronic overactivation of the RAS does not primarily contribute to the early aging phenotypes of skeletal muscle in ACE2KO mice.

Aims/Introduction Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β‐cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α‐cells. Materials and Methods Experiments were carried out in high‐fat, high‐sucrose diet‐fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme‐linked immunosorbent assay; the latter eliminates cross‐reactivities with other proglucagon‐derived peptides. Results Plasma glucagon, insulin and glucagon‐like peptide‐1 levels were increased by imeglimin administration in high‐fat, high‐sucrose diet‐fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long‐term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long‐term administration of imeglimin did not alter α‐cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein‐1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I. Conclusions Overall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation. Imeglimin enhanced glucagon secretion through an indirect mechanism. Imeglimin improved fatty liver by suppressing sterol regulatory element binding protein‐1c expression in the liver. Plasma glucagon levels measured using the standard protocol of Mercodia sandwich enzyme‐linked immunosorbent assay might be falsely higher in cases with increased plasma proglucagon‐derived peptide levels.