REST Inactivation and Coexpression of ASCL1 and POU3F4 Are Necessary for the Complete Transformation of RB1/TP53-Inactivated Lung Adenocarcinoma into Neuroendocrine Carcinoma.

Although recent reports have revealed the importance of the inactivation of both RB1 and TP53 in the transformation from lung adenocarcinoma into neuroendocrine carcinoma (NEC), the requirements for complete transformation into NEC have not been elucidated. To investigate alterations in the characteristics associated with the inactivation of RB1/TP53 and define the requirements for transformation into NEC cells, RB1/TP53 double-knockout A549 lung adenocarcinoma cells were established, and additional knockout of REST and transfection of ASCL1 and POU class 3 homeobox transcription factors (TFs) was conducted. More than 60 genes that are abundantly expressed in neural cells and several genes associated with epithelial-to-mesenchymal transition were up-regulated in RB1/TP53 double-knockout A549 cells. Although the expression of chromogranin A and synaptophysin was induced by additional knockout of REST (which mimics the status of most NECs), the expression of another neuroendocrine marker, CD56, and proneural TFs was not induced. However, coexpression of ASCL1 and POU3F4 in RB1/TP53/REST triple-knockout A549 cells induced the expression of not only CD56 but also other proneural TFs (NEUROD1 and insulinoma-associated 1) and induced NEC-like morphology. These findings suggest that the inactivation of RB1 and TP53 induces a state necessary for the transformation of lung adenocarcinoma into NEC and that further inactivation of REST and coexpression of ASCL1 and POU3F4 are the triggers for complete transformation into NEC.

Paclitaxel sensitizes homologous recombination-proficient ovarian cancer cells to PARP inhibitor via the CDK1/BRCA1 pathway.

OBJECTIVE: An effective treatment strategy for epithelial ovarian cancer (EOC) with homologous recombination (HR)-proficient (HRP) phenotype has not been established, although poly (ADP-ribose) polymerase inhibitors (PARPi) impact the disease course with HR-deficient (HRD) phenotype. Here, we aimed to clarify the cellular effects of paclitaxel (PTX) on the DNA damage response and the therapeutic application of PTX with PARPi in HRP ovarian cancer. METHODS: Two models with different PTX dosing schedules were established in HRP ovarian cancer OVISE cells. Growth inhibition and HR activity were analyzed in these models with or without PARPi. BRCA1 phosphorylation status was examined in OVISE cells by inhibiting CDK1, which was reduced by PTX treatment. CDK1 expression was evaluated in EOC patients treated with PTX-based neoadjuvant chemotherapy. RESULTS: PTX suppressed CDK1 expression resulting in impaired BRCA1 phosphorylation in OVISE cells. The reduced CDK1 activity by PTX could decrease HR activity in response to DNA damage and therefore increase the sensitivity to PARPi. Immunohistochemistry showed that CDK1 expression was attenuated in samples collected after PTX-based chemotherapy compared to those collected before chemotherapy. The decrease in CDK1 expression was greater with dose-dense PTX schedule than with the conventional PTX schedule. CONCULSIONS: PTX could act synergistically with PARPi in HRP ovarian cancer cells, suggesting that the combination of PTX with PARPi may be a novel treatment strategy extending the utility of PARPi to EOC. Our findings provide cules for future translational clinical trials evaluating the efficacy of PTX in combination with PARPi in HRP ovarian cancer.

Clinical outcomes in pregnant women with coronavirus disease 2019 in a perinatal medical centre in Japan: a retrospective study of the first 1 year of the pandemic.

In this retrospective study, we analysed clinical and demographic data from the medical records of 31 pregnant women with coronavirus disease 2019 (COVID-19) who were treated at our hospital between April 2020 and April 2021. The most common symptom was a fever; ∼10% of patients were asymptomatic. One patient with rapidly worsening pneumonia needed a Caesarean Section at 30 weeks and was admitted for intensive care. Twelve patients received perinatal care in our hospital (10 live births, one stillbirth, and one artificial abortion). Six patients delivered vaginally; the others delivered via caesarean section. Two patients had complications, including severe hypertensive disorders and preeclampsia. All patients recovered from COVID-19. Severe acute respiratory syndrome coronavirus 2 was not detected in the placenta, umbilical cord, cord blood, amniotic fluid, vaginal fluid, or breast milk in any patient. There were no neonatal adverse outcomes. The possibility of transmitting the coronavirus to pregnancy-related samples was low.IMPACT STATEMENTWhat is already known on the subject? COVID-19 has been affecting different countries in diverse ways, and the incidence, mortality, and morbidity rates of patients with COVID-19 vary widely by country or region and race. These differences in results may reflect racial differences and differences in national health care systems. Moreover, the information about the perinatal outcomes of pregnant women with COVID-19 and their newborns from Japan is limited.What do the results of this study add to what is known? We described the perinatal outcomes of 31 Japanese pregnant women with COVID-19 who were managed safely in a perinatal medical centre in Tokyo Japan, during the first 1 year of the pandemic.What are the implications of these findings for clinical practice and/or further research? Severe pneumonia and perinatal complications may occur, although no maternal and neonatal deaths were observed for COVID-19-positive pregnant women in our facility. Therefore, it is important to prevent this infection during pregnancy with the provision of effective medical care.

Efficient Actor-Critic Reinforcement Learning With Embodiment of Muscle Tone for Posture Stabilization of the Human Arm.

This letter proposes a new idea to improve learning efficiency in reinforcement learning (RL) with the actor-critic method used as a muscle controller for posture stabilization of the human arm. Actor-critic RL (ACRL) is used for simulations to realize posture controls in humans or robots using muscle tension control. However, it requires very high computational costs to acquire a better muscle control policy for desirable postures. For efficient ACRL, we focused on embodiment that is supposed to potentially achieve efficient controls in research fields of artificial intelligence or robotics. According to the neurophysiology of motion control obtained from experimental studies using animals or humans, the pedunculopontine tegmental nucleus (PPTn) induces muscle tone suppression, and the midbrain locomotor region (MLR) induces muscle tone promotion. PPTn and MLR modulate the activation levels of mutually antagonizing muscles such as flexors and extensors in a process through which control signals are translated from the substantia nigra reticulata to the brain stem. Therefore, we hypothesized that the PPTn and MLR could control muscle tone, that is, the maximum values of activation levels of mutually antagonizing muscles using different sigmoidal functions for each muscle; then we introduced antagonism function models (AFMs) of PPTn and MLR for individual muscles, incorporating the hypothesis into the process to determine the activation level of each muscle based on the output of the actor in ACRL. ACRL with AFMs representing the embodiment of muscle tone successfully achieved posture stabilization in five joint motions of the right arm of a human adult male under gravity in predetermined target angles at an earlier period of learning than the learning methods without AFMs. The results obtained from this study suggest that the introduction of embodiment of muscle tone can enhance learning efficiency in posture stabilization disorders of humans or humanoid robots.

Muscle Synergy-Driven Robust Motion Control.

Humans are able to robustly maintain desired motion and posture under dynamically changing circumstances, including novel conditions. To accomplish this, the brain needs to optimize the synergistic control between muscles against external dynamic factors. However, previous related studies have usually simplified the control of multiple muscles using two opposing muscles, which are minimum actuators to simulate linear feedback control. As a result, they have been unable to analyze how muscle synergy contributes to motion control robustness in a biological system. To address this issue, we considered a new muscle synergy concept used to optimize the synergy between muscle units against external dynamic conditions, including novel conditions. We propose that two main muscle control policies synergistically control muscle units to maintain the desired motion against external dynamic conditions. Our assumption is based on biological evidence regarding the control of multiple muscles via the corticospinal tract. One of the policies is the group control policy (GCP), which is used to control muscle group units classified based on functional similarities in joint control. This policy is used to effectively resist external dynamic circumstances, such as disturbances. The individual control policy (ICP) assists the GCP in precisely controlling motion by controlling individual muscle units. To validate this hypothesis, we simulated the reinforcement of the synergistic actions of the two control policies during the reinforcement learning of feedback motion control. Using this learning paradigm, the two control policies were synergistically combined to result in robust feedback control under novel transient and sustained disturbances that did not involve learning. Further, by comparing our data to experimental data generated by human subjects under the same conditions as those of the simulation, we showed that the proposed synergy concept may be used to analyze muscle synergy-driven motion control robustness in humans.

Finite element analysis of biological soft tissue surrounded by a deformable membrane that controls transmembrane flow.

BACKGROUND: Many biological soft tissues are hydrated porous hyperelastic materials, which consist of a complex solid skeleton with fine voids and fluid filling these voids. Mechanical interactions between the solid and the fluid in hydrated porous tissues have been analyzed by finite element methods (FEMs) in which the mixture theory was introduced in various ways. Although most of the tissues are surrounded by deformable membranes that control transmembrane flows, the boundaries of the tissues have been treated as rigid and/or freely permeable in these studies. The purpose of this study was to develop a method for the analysis of hydrated porous hyperelastic tissues surrounded by deformable membranes that control transmembrane flows. RESULTS: For this, we developed a new nonlinear finite element formulation of the mixture theory, where the nodal unknowns were the pore water pressure and solid displacement. This method allows the control of the fluid flow rate across the membrane using Neumann boundary condition. Using the method, we conducted a compression test of the hydrated porous hyperelastic tissue, which was surrounded by a flaccid impermeable membrane, and a part of the top surface of this tissue was pushed by a platen. The simulation results showed a stress relaxation phenomenon, resulting from the interaction between the elastic deformation of the tissue, pore water pressure gradient, and the movement of fluid. The results also showed that the fluid trapped by the impermeable membrane led to the swelling of the tissue around the platen. CONCLUSIONS: These facts suggest that our new method can be effectively used for the analysis of a large deformation of hydrated porous hyperelastic material surrounded by a deformable membrane that controls transmembrane flow, and further investigations may allow more realistic analyses of the biological soft tissues, such as brain edema, brain trauma, the flow of blood and lymph in capillaries and pitting edema.

[A Case of Metachronous Cancer Originating from Five Different Organs].

Advances and improvements in the early detection, diagnosis, and treatment modalities have increased the opportunities to treat multiple primary malignancies. Herein, we report a male patient with five metachronous cancers. The patient had initially undergone partial tongue resection for tongue cancer in 2003 at the age of 57 years and was subsequently diagnosed with acute promyelocytic leukemia, duodenal cancer, prostate cancer, and bladder cancer, over a period of 13 years. The patient underwent androgen deprivation therapy and palliative radiation therapy for the management of metastatic prostate cancer in 2016. The poor prognosis of the patient was thought to be related to be the prostate cancer because the other cancers were either in remission or localized. The occurrence of five metachronous cancers is extremely rare, and this is the fourth case to be reported in the Japanese literature.

Prognostic impact of interleukin-6 expression in stage I ovarian clear cell carcinoma.

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) frequently presents at an early stage. In stage I OCCC, the prognosis differs according to substage. In particular, predictive biomarkers and new treatment strategies are needed for stage IC2/IC3 disease. We investigated tumor biology and prognostic factors for stage I OCCC from a clinicopathological perspective, including the expression of ARID1A and IL-6, which are considered critical for OCCC carcinogenesis. METHODS: A retrospective cohort study of 192 patients with stage I OCCC treated at a single institution was performed. We calculated overall survival (OS) with respect to 12 clinicopathological parameters that included the unique and diverse histological features of OCCC. RESULTS: The estimated 5-year OS rate in patients with all stage I OCCC was 88.9% during a median of 91months of follow-up. The multivariate analysis indicated that substage classification and IL-6 expression status were associated with poor OS (p=0.010 and p=0.027, respectively). Loss of ARID1A expression had no impact on survival; however, it was associated with substage (p=0.001), capsule rupture status (p=0.011), and ascites cytology (p=0.016). No clear association was found between ARID1A and IL-6 expressions. Histological findings, including the presence of endometriosis, adenofibroma, architectural pattern, and tumor cell type, showed no prognostic effects. CONCLUSIONS: Both substage classification and IL-6 expression status may be independent prognostic factors in stage I OCCC. Therefore, IL-6 molecular stratification may be crucial in optimizing therapeutic strategies for early stage OCCC to improve survival.

ARID1A expression in ovarian clear cell carcinoma with an adenofibromatous component.

AIMS: The carcinogenesis of ovarian clear cell carcinoma (CCC) has been hypothesized to comprise two different pathways: an adenofibroma-carcinoma sequence and an endometriosis-carcinoma sequence. However, the difference in the genetic basis of these two pathways remains unclear. Recent studies have suggested that an ARID1A mutation and the loss of the corresponding protein, BAF250a, are frequent events in CCC. Herein, we investigated the difference in the loss of BAF250a expression in adenofibroma-related CCC and endometriosis-related CCC. METHODS AND RESULTS: In total, 93 cases of surgically treated CCC were evaluated. The presence of adenofibroma and endometriosis associated with carcinoma was determined by reviewing haematoxylin and eosin-stained slides for each case. BAF250a expression in carcinoma was examined immunohistochemically. The loss of BAF250a expression was detected in carcinomas in 50 of 93 (54%) cases, including five of 18 (28%) with adenofibroma alone, 30 of 45 (67%) with endometriosis alone, eight of 18 (44%) with both conditions and seven of 12 (58%) with neither condition. The loss of BAF250a expression was significantly less frequent in CCC cases with adenofibroma than in cases with endometriosis (P = 0.01, Fisher's exact test). CONCLUSIONS: The action of ARID1A in carcinogenesis differs between adenofibroma-related CCC and endometriosis-related CCC.

Concordance Between Biopsy and Resection Diagnoses of Uterine Cervical Adenocarcinoma According to the Updated World Health Organization 2020 Classification: A Multi-Institutional Study Elucidating Real-World Practice in Japan.

CONTEXT.­: Endocervical adenocarcinoma is divided into human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) in the 5h edition of the World Health Organization (WHO) tumor classification launched in 2020. However, the validity of the morphological criteria used for biopsy specimens in real-world practice remains undetermined. OBJECTIVE.­: To validate the utility of the 5th edition of the WHO classification for biopsy samples, focusing on its diagnostic criteria with the aid of ancillary studies. DESIGN.­: We retrieved 217 cases of endocervical adenocarcinoma from 6 institutions, in which glass slides of both biopsy and resection specimens were available for review. Concordance between the biopsy and resection specimen diagnoses was evaluated. For discordant diagnoses, an algorithmic approach with ancillary studies proposed by the international group was applied to confirm their utility to improve the accuracy of biopsy diagnosis. RESULTS.­: The biopsy diagnosis matched the resection specimen diagnosis in 197 cases (concordance rate, 91%; κ = 0.75). The concordance rate was significantly higher for HPVA than HPVI (95% versus 81%, P = .001). There were no significant differences in the proportions of HPVA and HPVI or the accuracy of biopsy diagnosis between the participating institutions. All 19 discordant cases with unstained glass slides available were accurately recategorized as HPVA or HPVI using HPV in situ hybridization; p16 immunohistochemistry was positive in 3 of 9 cases of gastric-type HPVI that were negative by in situ hybridization. CONCLUSIONS.­: The 5th edition of the WHO criteria for biopsy diagnosis of endocervical adenocarcinoma distinguishes HPVA from HPVI well when ancillary studies are adequately applied.

Lens capsule pathological characteristics in cases of intraocular lens dislocation with atopic dermatitis.

PURPOSE: To explore lens capsule pathological characteristics in intraocular lens (IOL) dislocation after cataract surgery in patients with atopic dermatitis (AD). SETTING: University hospital department of ophthalmology. DESIGN: Case series with clinicopathological correlations. METHODS: Lens capsules and surrounding tissues excised during surgery from eyes with AD (AD group) and eyes without AD (non-AD group) with IOL dislocation were histologically evaluated. Hematoxylin and eosin staining was used to assess abnormal changes in lens epithelial cells (LECs). Masson trichrome staining distinguished the fibrous metaplasia around the lens capsule into high-density and low-density fibrosis. Capsular splitting (thinning) was identified in both stained preparations. RESULTS: The IOL dislocation morphology in the AD group (10 eyes of 10 patients) included 7 cases of capsular bag dislocation (CBD) and 3 cases of dead bag syndrome (DBS), with an average duration to IOL dislocation of 11.5 ± 5.6 years. All patients in the non-AD group (12 eyes of 12 patients) had CBD, averaging 10.2 ± 5.7 years to dislocation. Abnormal LECs, low-density fibrosis, and capsular splitting were observed in 9 (90), 9 (90), and 6 (60) of the patients in the AD group compared with 6 (50), 3 (25), and 2 (18), respectively, in the non-AD group (total n [%]). CONCLUSIONS: Compared with the non-AD group, the AD group exhibited higher frequencies of morphological changes in LECs, low-density fibrosis around the lens capsule, and capsular splitting characteristics of DBS. These results suggest LEC degeneration and increased lens capsule fragility occurred in patients with AD.

Respiratory entrainment of the locus coeruleus modulates arousal level to avoid physical risks from external vibration.

Slow rocking chairs can easily put people to sleep, while violent shaking, such as during earthquakes, may lead to rapid awakening. However, the influence of external body vibrations on arousal remains unclear. Herein, a computational model of a locus coeruleus (LC)-norepinephrine (NE) system and cardio-respiratory system were used to show that respiratory entrainment of the LC modulates arousal levels, which is an adaptation to avoid physical risks from external vibration. External vibrations of sinusoidal waves with different frequencies ranging from 0.1 to 20 [Hz] were applied to the LC based on the results of previous studies. We found that respiratory entrainment of the LC decreased the breathing rate (BR) and heart rate (HR) to maintain the HR within its normal range. Furthermore, 1:1 phase locking enhanced arousal level while phase-amplitude coupling decreased it for larger vibration stimuli. These findings suggest that respiratory entrainment of the LC might automatically modulate cardio-respiratory system homeostasis and arousal levels for performance readiness (fight/flight or freeze) to avoid physical risks from larger external vibrations.

Validity of the 2014 FIGO Stage IIIA1 Subclassification for Ovarian, Fallopian Tube, and Peritoneal Cancers.

BACKGROUND/AIM: The 2014 International Federation of Gynecology and Obstetrics (FIGO) classification subdivides patients with stage IIIA1 ovarian, fallopian tube, and peritoneal cancers by the greatest dimension of metastatic lymph node without supporting evidence. This study aimed to assess the validity of this subdivision. PATIENTS AND METHODS: A retrospective single-institution cohort study was performed in patients with ovarian, fallopian tube, or peritoneal cancer from 2009 to 2020. We compared outcomes between patients diagnosed with IIIA1(i) (metastasis ≤10 mm in the greatest dimension) and IIIA1(ii) (metastasis >10 mm in the greatest dimension). RESULTS: Of the 895 patients, 46 (5.1%) were classified as stage IIIA1, 20 as IIIA1(i), and 26 as IIIA1(ii). In stage IIIA1(ii), there were significantly more cases of serous carcinoma (p<0.001), and the number of positive nodes and lymph node ratio were significantly higher than those in stage IIIA1(i) (p=0.001, p=0.002). Five-year progression-free survival was 68.7% in patients with stage IIIA1(i) cancer and 58.1% in those with stage IIIA1(ii) (p=0.58). Five-year overall survival was 83.1% in patients with stage IIIA1(i) cancer and 80.2% in those with stage IIIA1(ii) (p=0.44). Among other patient characteristics and pathologic findings, there were no prognostic factors for patients with stage IIIA1 cancer. CONCLUSION: In this retrospective cohort study, further classification of FIGO stage IIIA1 cancer was not significantly associated with patient outcomes.

Endocrine secretory granule production is caused by a lack of REST and intragranular secretory content and accelerated by PROX1.

Endocrine secretory granules (ESGs) are morphological characteristics of endocrine/neuroendocrine cells and store peptide hormones/neurotransmitters. ESGs contain prohormones and ESG-related molecules, mainly chromogranin/secretogranin family proteins. However, the precise mechanism of ESG formation has not been elucidated. In this study, we experimentally induced ESGs in the non-neuroendocrine lung cancer cell line H1299. Since repressive element 1 silencing transcription factor (REST) and prospero homeobox 1 (PROX1) are closely associated with the expression of ESG-related molecules, we edited the REST gene and/or transfected PROX1 and then performed molecular biology, immunocytochemistry, and electron and immunoelectron microscopy assays to determine whether ESG-related molecules and ESGs were induced in H1299 cells. Although chromogranin/secretogranin family proteins were induced in H1299 cells by knockout of REST and the induction was accelerated by the PROX1 transgene, the ESGs could not be defined by electron microscopy. However, a small number of ESGs were detected in the H1299 cells lacking REST and expressing pro-opiomelanocortin (POMC) by electron microscopy. Furthermore, many ESGs were produced in the REST-lacking and PROX1- and POMC-expressing H1299 cells. These findings suggest that a lack of REST and the expression of genes related to ESG content are indispensable for ESG production and that PROX1 accelerates ESG production.Trial registration: Not applicable.

Computational approach to understand temporal and spatial tactile transmission processes from mechanical stimuli of the index fingertip to the primary somatosensory cortex.

Mechanisms of information transmission using tactile sense are one of major concerns in producing simulated experience in virtual or augmented reality as well as in compensating elderly or impaired people with diminished tactile sensory function. However, important mechanism of the difference of peak latency in the primary somatosensory cortex (SI) between electrical and mechanical stimulations of finger skin is not fully understood. We propose a computational approach to fuse a computational model to simulate temporal and spatial transmission processes from mechanical stimuli to the SI and experimental method using a magnetoencephalograph (MEG). In our model, a tactile model that combined a three-dimensional mechanical model of fingertip skin and a neurophysiological model of a slowly adapting type 1 (SA1) mechanoreceptor was integrated with a somatosensory evoked field (SEF) response model. Electrical and mechanical stimulations were applied to the same locations of the right or left index fingertips of three subjects using a MEG. By identifying parameters of the SEF response model using the electrical stimulation test data, predicted first peak latency due to a mechanical stimulus was identical to its average value obtained from the mechanical stimulation test data, while the spatial map predicted at the multiple SA1 receptors qualitatively corresponded to the MEG image map in the timings of peak latency. This suggests that mechanical change in the skin and neurophysiological responses generate the difference of peak latency in SI between electrical and mechanical stimulations. The computational approach has the potential for detailed investigation of mechanisms of tactile information transmission.

Investigation of dynamic deformation of the midbrain in rear-end collision using human brain FE model.

Mild traumatic brain injury (TBI), including concussions, can cause symptoms affecting physical or cognitive domains in the acute and chronic phases. In this study, we investigated the dynamic deformation of the brain stem, which might be important for these symptoms, using a human brain finite element model through reconstruction simulations of rear-end collisions in three different velocities. In all simulations, high maximum principal strain values were observed at the midbrain that were higher than those in the corpus callosum. These findings could provide some mechanical insights into brain disorders associated with mild TBI.

The effect of posterior tethers on the biomechanics of proximal junctional kyphosis: The whole human finite element model analysis.

Little is known about the effects of posterior tethers on the development of proximal junctional kyphosis (PJK). We evaluated the ability of posterior tethers to the proximal motion segment stiffness in long instrumented spinal instrumentation and fusion using a whole body human FE model. A series of finite element (FE) analysis of long segmental spinal fusion (SF) from the upper thoracic vertebra (T1) or lower thoracic vertebra (T9) to the sacrum with pedicle screws and rods were performed using an entire human body FE model (includes 234,910 elements), and compressive stresses (CS) on the anterior column, and tensile stresses (TS) on the posterior ligamentous complex (PLC) in the upper-instrumented vertebra (UIV) and the vertebra adjacent to the UIV (UIV + 1) were evaluated with posterior tethers or without posterior tethers. The models were tested at three T1 tilts (0, 20, 40 deg.), with 20% muscle contraction. Deformable material models were assigned to all body parts. Muscle-tendon complexes were modeled by truss elements with a Hill-type muscle material model. The CS of anterior column decreased with increasing T1 slope with tethers in both models, while the CS remained relatively large in T9 model compared with T1 model (T1 UIV; 0.96 to 1.56 MPa, T9 UIV; 4.79 to 5.61 MPa). The TS of the supraspinous ligament was markedly reduced in both T1 and T9 models with posterior tethers (11-35%). High vertebral CS on UIV and UIV + 1 were seen in the T9 UIV model, and the TS on the PLC were increased in both UIV models. Posterior tethers may decrease PJK development after SF with a proximal thoracic UIV, while both posterior tethers and vertebral augmentation may be necessary to reduce PJK development with a lower thoracic UIV.

Human Brain Modeling with Its Anatomical Structure and Realistic Material Properties for Brain Injury Prediction.

Impairments of executive brain function after traumatic brain injury (TBI) due to head impacts in traffic accidents need to be obviated. Finite element (FE) analyses with a human brain model facilitate understanding of the TBI mechanisms. However, conventional brain FE models do not suitably describe the anatomical structure in the deep brain, which is a critical region for executive brain function, and the material properties of brain parenchyma. In this study, for better TBI prediction, a novel brain FE model with anatomical structure in the deep brain was developed. The developed model comprises a constitutive model of brain parenchyma considering anisotropy and strain rate dependency. Validation was performed against postmortem human subject test data associated with brain deformation during head impact. Brain injury analyses were performed using head acceleration curves obtained from reconstruction analysis of rear-end collision with a human whole-body FE model. The difference in structure was found to affect the regions of strain concentration, while the difference in material model contributed to the peak strain value. The injury prediction result by the proposed model was consistent with the characteristics in the neuroimaging data of TBI patients due to traffic accidents.

Uncommon Human Telomerase Reverse Transcriptase Promoter Mutations Are Associated With Poor Survival in Ovarian Clear Cell Carcinoma.

OBJECTIVES: The present study assessed whether human telomerase reverse transcriptase (TERT) promoter mutations mediate the increased mortality risk observed in patients with ovarian clear cell carcinoma (CCC) and characterized the pathologic features of TERT promoter mutation-associated ovarian CCC. METHODS: The TERT promoter region in genomic DNA extracted from paraffin-embedded ovarian CCC specimens (n = 93) was bidirectionally sequenced. RESULTS: A total of 24 TERT promoter mutations were identified among the analyzed CCC cases, of which 11 were known "hotspot" mutations whose frequency was increased in CCC cases with compared to without coexistent adenofibroma (P < .05). In contrast, the 14 (including three novel) identified uncommon site mutations were shown to be associated with a poor progression-free survival rate (P < .01). CONCLUSIONS: The identified uncommon TERT promoter mutations exacerbate the poor prognosis characteristic of ovarian CCC cases, and the hotspot mutations appear to be a molecular feature of the adenofibroma-associated form of the disease.