Wild-Type Transthyretin Cardiac Amyloidosis is Not Rare in Elderly Subjects: the CATCH Screening Study.

BACKGROUND: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) affects older adults and is currently considered as a rare disorder. OBJECTIVE: We investigated for the first time the prevalence of ATTRwt-CA in elderly individuals from the general population. METHODS: General practitioners from Pisa, Italy, proposed a screening for ATTRwt-CA to all their patients aged 65-90 years, until 1,000 accepted. The following red flags were searched: interventricular septal thickness ≥12 mm, any echocardiographic, ECG or clinical hallmark of CA, or high sensitivity-troponin T ≥14 ng/L. Individuals with at least one red flag (n=346) were asked to undergo the search for a monoclonal protein and bone scintigraphy, and 216 accepted. RESULTS: Four patients received a non-invasive diagnosis of ATTRwt-CA. All complained of dyspnea on moderate effort. A woman and a man aged 79 and 85 years, respectively, showed an intense cardiac tracer uptake (grade 3), left ventricular (LV) wall thickening, grade 2 to 3 diastolic dysfunction, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) >1,000 ng/L. Two other patients (a man aged 74 years and a woman aged 83 years) showed a grade 2 uptake, an increased LV septal thickness, but preserved diastolic function, and NT-proBNP <300 ng/L. The prevalence of ATTR-CA in subjects ≥65 years was calculated as 0.46% (i.e., 4 out of the 870 subjects completing the screening, namely 654 not meeting the criteria for Step 2 and 216 progressing to Step 2). CONCLUSIONS: ATTRwt-CA is uncommon in elderly subjects from the general population, but more frequent than expected for a rare disease.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a heart condition mostly found in older adults. ATTRwt-CA is considered a rare disease, although no systematic screening have been performed yet. The study aimed to understand how common this disease is among the general population aged 65 to 90 years in Pisa, Italy. To do this, general practitioners offered screening for ATTRwt-CA to their patients within this age group. The initial step of the screening involved checking for certain warning signs (red flags), like abnormal thickness in a part of the heart called the interventricular septum, unusual heart function observed through various tests, or elevated levels of a specific heart protein. Out of 1,000 individuals who began the screening process, 346 showed at least one of these red flags and were further examined using bone scintigraphy (a type of imaging test) and tests for a specific protein related to this condition. Of these, 216 agreed to proceed with these additional tests. The results showed that four of these patients actually had ATTRwt-CA. Their conditions varied in severity, with some showing more intense signs of the disease on the heart scans, thicker heart walls, and higher levels of heart stress proteins. All four patients experienced mild difficulty in breathing during physical activity. Based on these findings, the study concluded that about 0.46% of elderly individuals in the general population might have ATTRwt-CA, indicating that the disease is somewhat more common in this age group than previously thought.

MRCK as a Potential Target for Claudin-Low Subtype of Breast Cancer.

To find new molecular targets for triple negative breast cancer (TNBC), we analyzed a large-scale drug screening dataset based on breast cancer subtypes. We discovered that BDP-9066, a specific MRCK inhibitor (MRCKi), may be an effective drug against TNBC. After confirming the efficacy and specificity of BDP-9066 against TNBC in vitro and in vivo, we further analyzed the underlying mechanism of specific activity of BDP-9066 against TNBC. Comparing the transcriptome of BDP-9066-sensitive and -resistant cells, the activation of the focal adhesion and YAP/TAZ pathway were found to play an important role in the sensitive cells. Furthermore, YAP/TAZ is indeed repressed by BDP-9066 in the sensitive cells, and active form of YAP suppresses the effects of BDP-9066. YAP/TAZ expression and activity are high in TNBC, especially the Claudin-low subtype, consistent with the expression of focal adhesion-related genes. Interestingly, NF-κB functions downstream of YAP/TAZ in TNBC cells and is suppressed by BDP-9066. Furthermore, the PI3 kinase pathway adversely affected the effects of BDP-9066 and that alpelisib, a PI3 kinase inhibitor, synergistically increased the effects of BDP-9066, in PIK3CA mutant TNBC cells. Taken together, we have shown for the first time that MRCKi can be new drugs against TNBC, particularly the Claudin-low subtype.

Optimizing age-related hearing risk predictions: an advanced machine learning integration with HHIE-S.

OBJECTIVES: The elderly are disproportionately affected by age-related hearing loss (ARHL). Despite being a well-known tool for ARHL evaluation, the Hearing Handicap Inventory for the Elderly Screening version (HHIE-S) has only traditionally been used for direct screening using self-reported outcomes. This work uses a novel integration of machine learning approaches to improve the predicted accuracy of the HHIE-S tool for ARHL in older adults. METHODS: We employed a dataset that was gathered between 2016 and 2018 and included 1,526 senior citizens from several Taipei City Hospital branches. 80% of the data were used for training (n = 1220) and 20% were used for testing (n = 356). XGBoost, Gradient Boosting, and LightGBM were among the machine learning models that were only used and assessed on the training set. In order to prevent data leakage and overfitting, the Light Gradient Boosting Machine (LGBM) model-which had the greatest AUC of 0.83 (95% CI 0.81-0.85)-was then only used on the holdout testing data. RESULTS: On the testing set, the LGBM model showed a strong AUC of 0.82 (95% CI 0.79-0.86), far outperforming conventional techniques. Notably, several HHIE-S items and age were found to be significant characteristics. In contrast to traditional HHIE research, which concentrates on the psychological effects of hearing loss, this study combines cutting-edge machine learning techniques-specifically, the LGBM classifier-with the HHIE-S tool. The incorporation of SHAP values enhances the interpretability of the model's predictions and provides a more comprehensive comprehension of the significance of various aspects. CONCLUSIONS: Our methodology highlights the great potential that arises from combining machine learning with validated hearing evaluation instruments such as the HHIE-S. Healthcare practitioners can anticipate ARHL more accurately thanks to this integration, which makes it easier to intervene quickly and precisely.

The anti-platelet drug cilostazol enhances heart rate and interrenal steroidogenesis and exerts a scant effect on innate immune responses in zebrafish.

RATIONALE: Cilostazol, an anti-platelet phosphodiesterase-3 inhibitor used for the treatment of intermittent claudication, is known for its pleiotropic effects on platelets, endothelial cells and smooth muscle cells. However, how cilostazol impacts the endocrine system and the injury-induced inflammatory processes remains unclear. METHODS: We used the zebrafish, a simple transparent model that demonstrates rapid development and a strong regenerative ability, to test whether cilostazol influences heart rate, steroidogenesis, and the temporal and dosage effects of cilostazol on innate immune cells during tissue damage and repair. RESULTS: While dosages of cilostazol from 10 to 100 µM did not induce any noticeable morphological abnormality in the embryonic and larval zebrafish, the heart rate was increased as measured by ImageJ TSA method. Moreover, adrenal/interrenal steroidogenesis in larval zebrafish, analyzed by whole-mount 3ß-Hsd enzymatic activity and cortisol ELISA assays, was significantly enhanced. During embryonic fin amputation and regeneration, cilostazol treatments led to a subtle yet significant effect on reducing the aggregation of Mpx-expressing neutrophil at the lesion site, but did not affect the immediate injury-induced recruitment and retention of Mpeg1-expressing macrophages. CONCLUSIONS: Our results indicate that cilostazol has a significant effect on the heart rate and the growth as well as endocrine function of steroidogenic tissue; with a limited effect on the migration of innate immune cells during tissue damage and repair.

Minimal Clinically Important Difference (MCID) in the Functional Status Measures in Patients with Stroke: Inverse Probability Treatment Weighting.

This study proposed to evaluate the temporal trend, define the minimal clinically important difference (MCID) for five functional status measures, and identify risk factors for reaching deterioration in the MCID. This prospective cohort study analyzed 680 patients with ischemic stroke and 151 patients with hemorrhagic stroke at six hospitals between April 2015 and October 2021. All patients completed the functional status measures before rehabilitation (baseline), and at the 12th week and 2nd year after rehabilitation. Patients in the post-acute care (PAC) group exhibited significantly larger improvements for the functional status measures compared to those in the non-PAC group (p < 0.05). Patients with hemorrhagic stroke also displayed larger improvements in the functional status measures when compared to patients with ischemic stroke. Furthermore, the improvement in MCID ranged from 0.01 to 16.18 points when comparing baseline and the 12th week after rehabilitation, but the deterioration in MCID ranged from 0.38 to 16.12 points. Simultaneously, assessing the baseline and the second year after rehabilitation, the improvement in MCID ranged from 0.01 to 18.43 points, but the deterioration in MCID ranged from 0.68 to 17.26 points. Additionally, the PAC program, age, education level, body mass index, smoking, readmission within 30 days, baseline functional status score, use of Foley catheter and nasogastric tube, as well as a history of previous stroke are significantly associated with achieving deterioration in MCID (p < 0.05). These findings suggest that if the mean change scores of the functional status measures have reached the thresholds, the change scores can be perceived by patients as clinically important.

Shortened neural conduction time in young adults with tinnitus as revealed by chirp-evoked auditory brainstem response.

Tinnitus is generally considered to be caused by neuroplastic changes in the central nervous system, triggered by a loss of input from the damaged peripheral system; however, conflicting results on auditory brainstem responses (ABRs) to clicks have been reported previously in humans with tinnitus. This study aimed to compare the effect of tinnitus on ABRs to chirps with those to clicks in normal-hearing young adults with tinnitus. The results showed that the tinnitus group had no significantly poorer hearing thresholds (0.25-16 kHz), click-evoked otoacoustic emissions (1-16 kHz), and speech perception in noise (SPIN) than the control group. Although chirps evoked significantly larger wave I and V amplitudes than clicks, people with tinnitus had no significantly smaller wave I amplitudes for either stimulus. Nevertheless, adults with tinnitus exhibited significantly smaller interpeak interval (IPI) between waves I and V for chirps (IPI-chirp) but not for clicks. In addition, the IPI-chirp correlated significantly with the SPIN for individuals with tinnitus when the signal-to-noise ratio was low. The present results suggest that the chirp-evoked ABR may be a valuable clinical tool for objectively assessing the SPIN in individuals with tinnitus. Further studies should be conducted to investigate possible etiologies of tinnitus.

Muscleblind-like 2 knockout shifts adducin 1 isoform expression and alters dendritic spine dynamics of cortical neurons during brain development.

AIMS: Muscleblind-like 2 (MBNL2) plays a crucial role in regulating alternative splicing during development and mouse loss of MBNL2 recapitulates brain phenotypes in myotonic dystrophy (DM). However, the mechanisms underlying DM neuropathogenesis during brain development remain unclear. In this study, we aim to investigate the impact of MBNL2 elimination on neuronal development by Mbnl2 conditional knockout (CKO) mouse models. METHODS: To create Mbnl2 knockout neurons, cDNA encoding Cre-recombinase was delivered into neural progenitors of Mbnl2flox/flox mouse brains by in utero electroporation. The morphologies and dynamics of dendritic spines were monitored by confocal and two-photon microscopy in brain slices and live animals from the neonatal period into adulthood. To investigate the underlying molecular mechanism, we further detected the changes in the splicing and molecular interactions of proteins associated with spinogenesis. RESULTS: We found that Mbnl2 knockout in cortical neurons decreased dendritic spine density and dynamics in adolescent mice. Mbnl2 ablation caused the adducin 1 (ADD1) isoform to switch from adult to fetal with a frameshift, and the truncated ADD1 failed to interact with alpha-II spectrin (SPTAN1), a critical protein for spinogenesis. In addition, expression of ADD1 adult isoform compensated for the reduced dendritic spine density in cortical neurons deprived of MBNL2. CONCLUSION: MBNL2 plays a critical role in maintaining the dynamics and homeostasis of dendritic spines in the developing brain. Mis-splicing of downstream ADD1 may account for the alterations and contribute to the DM brain pathogenesis.

Mice lacking MBNL1 and MBNL2 exhibit sudden cardiac death and molecular signatures recapitulating myotonic dystrophy.

Myotonic dystrophy (DM) is caused by expansions of C(C)TG repeats in the non-coding regions of the DMPK and CNBP genes, and DM patients often suffer from sudden cardiac death due to lethal conduction block or arrhythmia. Specific molecular changes that underlie DM cardiac pathology have been linked to repeat-associated depletion of Muscleblind-like (MBNL) 1 and 2 proteins and upregulation of CUGBP, Elav-like family member 1 (CELF1). Hypothesis solely targeting MBNL1 or CELF1 pathways that could address all the consequences of repeat expansion in heart remained inconclusive, particularly when the direct cause of mortality and results of transcriptome analyses remained undetermined in Mbnl compound knockout (KO) mice with cardiac phenotypes. Here, we develop Myh6-Cre double KO (DKO) (Mbnl1-/-; Mbnl2cond/cond; Myh6-Cre+/-) mice to eliminate Mbnl1/2 in cardiomyocytes and observe spontaneous lethal cardiac events under no anesthesia. RNA sequencing recapitulates DM heart spliceopathy and shows gene expression changes that were previously undescribed in DM heart studies. Notably, immunoblotting reveals a nearly 6-fold increase of Calsequestrin 1 and 50% reduction of epidermal growth factor proteins. Our findings demonstrate that complete ablation of MBNL1/2 in cardiomyocytes is essential for generating sudden death due to lethal cardiac rhythms and reveal potential mechanisms for DM heart pathogenesis.

Are Electrocochleographic Changes an Early Sign of Cochlear Synaptopathy? A Prospective Study in Tinnitus Patients with Normal Hearing.

The mechanism of tinnitus accompanied by a normal audiogram remains elusive. This study aimed to investigate evidence of primary neural degeneration, also known as cochlear synaptopathy, in tinnitus patients with normal hearing thresholds. We analyzed the differences in electrocochleography (ECochG) measurements between normal-hearing subjects with and without tinnitus. Forty-five subjects were enrolled in this study: 21 were in the tinnitus group, defined by chronic tinnitus of over two months' duration with normal audiometric thresholds, and 24 were in the control group, defined by a lack of tinnitus complaints. Electrocochleograms were evoked by 1, 4, 6, and 8 kHz alternating-polarity tone bursts at sound pressure levels (SPLs) of 90−110 dB. The tinnitus group had smaller action potential (AP) amplitudes than the control group for 1, 4, 6, and 8 kHz tone bursts and showed significant amplitude reduction at 1 kHz 110 dB SPL (p < 0.01), 1 kHz 90 dB SPL (p < 0.05), and 4 kHz 110 dB SPL (p < 0.05). There were no significant differences in the summating potential/action potential (SP/AP) amplitude ratios across the four tested frequencies. A trend of reduced AP amplitudes was found in the tinnitus group, supporting the hypothesis that tinnitus might be associated with primary neural degeneration.

Evaluating auditory brainstem response to a level-dependent chirp designed based on derived-band latencies.

The best cochlear-neural delay model for designing a chirp that can produce the largest auditory brainstem response (ABR) has not been established. This study comprised two experiments. Experiment I aimed to estimate the delay model by measuring derived-band ABR latencies at different levels. The results demonstrated that, as the level decreased, the delay between the center frequencies of 0.7 and 5.7 kHz increased. The aim of experiment II was to compare ABRs generated by three stimuli: (1) a level-dependent derived-band (DB)-Chirp, designed based on the model in experiment I; (2) a level-dependent level specific (LS)-Chirp from Kristensen and Elberling [(2012). J. Am. Acad. Audiol. 23, 712-721]; and (3) a click. The results demonstrated that the DB-Chirp produced significantly larger wave V than the LS-Chirp at 45 dB normal hearing level (nHL); however, no differences were observed at other levels. The wave I generated by the DB-Chirp and LS-Chirp were significantly larger than those evoked by the click at 45 and 60 dB nHL and at 30 and 45 dB nHL, respectively; however, at all levels, no differences between these two chirps were observed. The DB-Chirp may be a valuable stimulus for producing ABRs for clinical applications such as assessing cochlear synaptopathy and estimating hearing sensitivity.

Smartphone-bundled earphones as personal sound amplification products in adults with sensorineural hearing loss.

Given the low prevalence of hearing aid use among individuals with hearing loss due to their high costs and social stigma, personal sound amplification products (PSAPs) may serve as alternatives with adequate hearing compensation and greater accessibility. This study examined the electroacoustic features of hearing aids and selected smartphone-bundled earphones, specifically AirPods, as PSAPs, and compared hearing performances among adults with mild-to-moderate hearing loss when aided with each hearing assistive device. Our results indicated that AirPods Pro met four out of five PSAP standards. No significant differences were found regarding speech perception between AirPods Pro and hearing aids in quiet but not with the presence of background noises. AirPods Pro may have the potential to be a hearing assistive device for adults with mild-to-moderate hearing loss. More research is needed to investigate the safety and feasibility of using earphones bundled with other smartphones as PSAPs.

Inverse Probability of Treatment Weighting in 5-Year Quality-of-Life Comparison among Three Surgical Procedures for Hepatocellular Carcinoma.

This prospective longitudinal cohort study analyzed long-term changes in individual subscales of quality-of-life (QOL) measures and explored whether these changes were related to effective QOL predictors after hepatocellular carcinoma (HCC) surgery. All 520 HCC patients in this study had completed QOL surveys before surgery and at 6 months, 2 years, and 5 years after surgery. Generalized estimating equation models were used to compare the 5-year QOL among the three HCC surgical procedures. The QOL was significantly (p < 0.05) improved at 6 months after HCC surgery but plateaued at 2−5 years after surgery. In postoperative surveys, the effect size was largest in the nausea and vomiting subscales in patients who had received robotic surgery, and the effect size was smallest in the dyspnea subscale in patients who had received open surgery. It revealed the following explanatory variables for postoperative QOL: surgical procedure type, gender, age, hepatitis C, smoking, tumor stage, postoperative recurrence, and preoperative QOL. The comparisons revealed that, when evaluating QOL after HCC surgery, several factors other than the surgery itself should be considered. The analysis results also implied that postoperative quality of life might depend not only on the success of the surgical procedure, but also on preoperative quality of life.

Diagnostic Validity of Self-Reported Hearing Loss in Elderly Taiwanese Individuals: Diagnostic Performance of a Hearing Self-Assessment Questionnaire on Audiometry.

KEY POINTS: Question: Can the traditional Chinese version of the hearing handicap inventory for elderly screening (HHIE-S) checklist screen for age-related hearing loss (ARHL) in elderly individuals? FINDINGS: In this cross-sectional study of 1696 Taiwanese patients who underwent annual government-funded geriatric health checkups, the Chinese version of the HHIE-S had a sensitivity of 76.9% and a specificity of 79.8% with a cutoff score greater than 6 for identifying patients with disabled hearing loss (defined as a PTA > 40 dB). Meaning: The traditional Chinese version of the HHIE-S is an effective test to detect ARHL and can improve the feasibility of large-scale hearing screening among elderly individuals. PURPOSE: The traditional Chinese version of the hearing handicap inventory for elderly screening (TC-HHIE-S) was translated from English and is intended for use with people whose native language is traditional Chinese, but its effectiveness and diagnostic performance are still unclear. The purpose of this study was to evaluate the validity and reliability of the traditional Chinese version of the HHIE-S for screening for age-related hearing loss (ARHL). METHODS: A total of 1696 elderly people underwent the government's annual geriatric medical examination at community hospitals. In this cross-sectional study, we recorded average conducted pure-tone averages (PTA) (0.5 kHz, 1 kHz, 2 kHz, 4 kHz), age, sex, and HHIE-S data. Receiver operating characteristic (ROC) curve analysis was used to identify the best critical point for detecting hearing impairment, and the validity of the structure was verified by the agreement between the TC-HHIE-S and PTA results. RESULTS: The HHIE-S scores were correlated with the better-ear pure-tone threshold averages (PTAs) at 0.5-4 kHz (correlation coefficient r = 0.45). The internal consistency of the total HHIE-S score was excellent (Cronbach's alpha = 0.901), and the test-retest reliability was also excellent (Spearman's correlation coefficient = 0.60, intraclass correlation coefficient = 0.75). In detecting disabled hearing loss (i.e., PTA at 0.5-4 kHz > 40 dB), the HHIE-S cutoff score of > 6 had a sensitivity of 76.9% and a specificity of 79.8%. CONCLUSIONS: The traditional Chinese version of the HHIE-S is a valid, reliable, and efficient tool for large-scale screening for ARHL.

Effect of referral systems on costs and outcomes after hip fracture surgery in Taiwan.

OBJECTIVE: To explore the economic burdens of hip fracture surgery in patients referred to lower-level medical institutions and to evaluate how referral systems affect costs and outcomes of hip fracture surgery. DESIGN: A nationwide population-based retrospective cohort study. SETTING: All hospitals in Taiwan. PARTICIPANTS: A total of 7500 patients who had received hip fracture surgery (International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) diagnostic codes 820.0 ∼ 820.9 and procedure codes 79.15, 79.35, 81.52, 81.53) performed in 1997 to 2013. MAIN OUTCOME MEASURES: Total costs including outpatient costs, inpatient costs and total medical costs and medical outcomes including 30-day readmission, 90-day readmission, infection, dislocation, revision and mortality. RESULTS: The patients were referred to a lower medical institution after hip fracture surgery (downward referral group) and 3034 patients continued treatment at the same medical institution (non-referral group). Demographic characteristics, clinical characteristics and institutional characteristics were significantly associated with postoperative costs and outcomes (P < 0.05). On average, the annual healthcare cost was New Taiwan Dollars (NT$)2262 per patient lower in the downward referral group compared with the non-referral group. The annual economic burdens of the downward referral group approximated NT$241 million (2019 exchange rate, NT$30.5 = US$1). CONCLUSIONS: Postoperative costs and outcomes of hip fracture surgery are related not only to demographic and clinical characteristics, but also to institutional characteristics. The advantages of downward referral after hip fracture surgery can save huge medical costs and provide a useful reference for healthcare authorities when drafting policies for the referral system.

Evaluating the Function of the Medial Olivocochlear Bundle in Patients With Bilateral Tinnitus.

Purpose No study has investigated the effects of contralateral noise (CN) on speech-in-noise perception (SINP) in listeners with tinnitus. The mechanisms underlying the involvement of medial olivocochlear (MOC) reflex with SINP remain to be elucidated. This study aimed to investigate the MOC function in patients with bilateral tinnitus by measuring distortion product otoacoustic emission and SINP. Method Eighteen patients with bilateral tinnitus (one male and 17 females; age: M ± SD = 45.61 ± 10.18 years) and 19 listeners without tinnitus (six males and 13 females; age: M ± SD = 34.11 ± 8.35 years) were recruited for the study. Each subject underwent distortion product otoacoustic emission measurement and the SINP test for both ears. The effects of CN on these two measurements were compared between tinnitus ears (TEs) and no-tinnitus ears (NTEs). Results The presence of CN significantly reduced distortion product (DP) amplitudes and improved SINP for TEs, and the amounts of DP suppression and SINP improvement were similar to those in NTEs. Improvement of SINP was positively correlated with DP suppression at 6185 Hz for NTEs and at 1640 Hz for TEs. Conclusions The results of this study suggest that the amounts of DP suppression and SINP improvement were similar between listeners with and without tinnitus. For both ear groups, the MOC reflex was involved with SINP at specific frequencies. Any clinical test outcomes with regard to the MOC bundle in patients with tinnitus should be interpreted with caution until further studies are conducted.

Cytoreduction surgery and hyperthermic intraperitoneal chemotherapy for treating advanced peritoneal metastases of hepatocellular carcinoma.

BACKGROUND: An effective treatment strategy for peritoneal metastasis (PM) of hepatocellular carcinoma (HCC-PM) has yet to be established. Although cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have shown favorable outcomes in certain malignancies, their role in peritoneal metastatic HCC is unclear. Herein, we present a series of patients with HCC-PM treated with CRS/HIPEC and evaluate their outcomes. METHODS: Records of patients with HCC-PM who had undergone CRS/HIPEC at the Hyperthermia Center of Yuan's General Hospital, Kaohsiung, Taiwan, between September 2015 and December 2016 were reviewed retrospectively. Patients were followed up until September 2019. We assessed the clinical courses and outcomes of these patients to clarify the benefits of CRS/HIPEC. RESULTS: Six patients were included in our study. HCC-PM occurred synchronously in one patient and occurred metachronously in five patients after therapeutic minimally invasive procedures, including radiofrequency ablation, laparoscopic hepatectomy, robotic hepatectomy or spontaneously. The median peritoneal cancer index was 18.5. All patients experienced complete peritoneal cytoreduction without perioperative mortality. One patient had two CTCAE grade 3 complications. The median follow-up was 16 months. The median overall survival was 15.7 months. Four patients died of lung metastasis or liver failure owing to intrahepatic recurrence. The survival rates observed at 1, 2, and 4 years were 66.7%, 33.3%, and 33.3%, respectively. CONCLUSIONS: CRS followed by HIPEC is feasible in patients with HCC-PM and might provide selected patients a chance for local disease control and longer survival. CRS/HIPEC might be considered as a treatment option in highly selected patients, as part of multimodal therapy approaches.

Artificial Neural Network and Cox Regression Models for Predicting Mortality after Hip Fracture Surgery: A Population-Based Comparison.

This study purposed to validate the accuracy of an artificial neural network (ANN) model for predicting the mortality after hip fracture surgery during the study period, and to compare performance indices between the ANN model and a Cox regression model. A total of 10,534 hip fracture surgery patients during 1996-2010 were recruited in the study. Three datasets were used: a training dataset (n = 7,374) was used for model development, a testing dataset (n = 1,580) was used for internal validation, and a validation dataset (1580) was used for external validation. Global sensitivity analysis also was performed to evaluate the relative importances of input predictors in the ANN model. Mortality after hip fracture surgery was significantly associated with referral system, age, gender, urbanization of residence area, socioeconomic status, Charlson comorbidity index (CCI) score, intracapsular fracture, hospital volume, and surgeon volume (p < 0.05). For predicting mortality after hip fracture surgery, the ANN model had higher prediction accuracy and overall performance indices compared to the Cox model. Global sensitivity analysis of the ANN model showed that the referral to lower-level medical institutions was the most important variable affecting mortality, followed by surgeon volume, hospital volume, and CCI score. Compared with the Cox regression model, the ANN model was more accurate in predicting postoperative mortality after a hip fracture. The forecasting predictors associated with postoperative mortality identified in this study can also bae used to educate candidates for hip fracture surgery with respect to the course of recovery and health outcomes.

DEAD-Box RNA Helicase 42 Plays a Critical Role in Pre-mRNA Splicing under Cold Stress.

Low temperature is an important environmental stress that adversely affects rice (Oryza sativa) growth and productivity. Splicing of pre-mRNA is a crucial posttranscriptional regulatory step in gene expression in plants and is sensitive to temperature. DEAD-box RNA helicases belong to an RNA helicase family involved in the rearrangement of ribonucleoprotein complexes and the modification of RNA structure and are therefore involved in all aspects of RNA metabolism. In this study, we demonstrate that the rate of pre-mRNA splicing is reduced in rice at low temperatures and that the DEAD-box RNA Helicase42 (OsRH42) is necessary to support effective splicing of pre-mRNA during mRNA maturation at low temperatures. OsRH42 expression is tightly coupled to temperature fluctuation, and OsRH42 is localized in the splicing speckles and interacts directly with U2 small nuclear RNA. Retarded pre-mRNA splicing and plant growth defects were exhibited by OsRH42-knockdown transgenic lines at low temperatures, thus indicating that OsRH42 performs an essential role in ensuring accurate pre-mRNA splicing and normal plant growth under low ambient temperature. Unexpectedly, our results show that OsRH42 overexpression significantly disrupts the pre-mRNA splicing pathway, causing retarded plant growth and reducing plant cold tolerance. Combined, these results indicate that accurate control of OsRH42 homeostasis is essential for rice plants to respond to changes in ambient temperature. In addition, our study presents the molecular mechanism of DEAD-box RNA helicase function in pre-mRNA splicing, which is required for adaptation to cold stress in rice.

Hinokitiol suppresses growth of B16 melanoma by activating ERK/MKP3/proteosome pathway to downregulate survivin expression.

Metastasis is the major cause of treatment failure in patients with cancer. Hinokitiol, a metal chelator derived from natural plants, has anti-inflammatory and antioxidant activities as well as anticancer effects. We investigated the potential anticancer effects of hinokitiol in metastatic melanoma cell line B16-F10. Exposure of the melanoma B16-F10 cells to hinokitiol significantly inhibited colony formation and cell viability in a time and concentration-dependent manner. The hinokitiol-treated cells exhibited apoptotic features in morphological assay. Results from Western blot and immunoprecipitation showed that hinokitiol treatment decreased survivin protein levels and increased suvivin ubiquitination. Pretreatment with proteosome inhibitors effectively prevented hinokitiol-induced decrease in survivin expression, implying that ubiquitin/proteosome pathway involved in hinokitiol-reduced survivin expression. Hinokitiol rapidly induced ERK phosphorylation followed by a sustained dephosphorylation, which accompanied with an increase in expression of tumor suppressor MKP-3 (mitogen-activated protein kinase phosphatase-3). Inhibition of hinokitiol-induced ERK activation by MEK inhibitor U0126 completely blocked expression of MKP-3. More importantly, inhibition of MKP-3 activity by NSC 95397 significantly inhibited hinokitiol-induced ERK dephosphorylation, ubiquitination and downregulation of survivin. These results suggested that hinokitiol inhibited growth of B16-F10 melanoma through downregulation of survivin by activating ERK/MKP-3/proteosome pathway. Hinokitiol-inhibition of survivin may be a novel and potential approach for melanoma therapy. Hinokitiol can be useful for developing therapeutic agent for melanoma.

Deficiency of lrp4 in zebrafish and human LRP4 mutation induce aberrant activation of Jagged-Notch signaling in fin and limb development.

Low-density lipoprotein receptor-related protein 4 (LRP4) is a multi-functional protein implicated in bone, kidney and neurological diseases including Cenani-Lenz syndactyly (CLS), sclerosteosis, osteoporosis, congenital myasthenic syndrome and myasthenia gravis. Why different LRP4 mutation alleles cause distinct and even contrasting disease phenotypes remain unclear. Herein, we utilized the zebrafish model to search for pathways affected by a deficiency of LRP4. The lrp4 knockdown in zebrafish embryos exhibits cyst formations at fin structures and the caudal vein plexus, malformed pectoral fins, defective bone formation and compromised kidney morphogenesis; which partially phenocopied the human LRP4 mutations and were reminiscent of phenotypes resulting form a perturbed Notch signaling pathway. We discovered that the Lrp4-deficient zebrafish manifested increased Notch outputs in addition to enhanced Wnt signaling, with the expression of Notch ligand jagged1b being significantly elevated at the fin structures. To examine conservatism of signaling mechanisms, the effect of LRP4 missense mutations and siRNA knockdowns, including a novel missense mutation c.1117C > T (p.R373W) of LRP4, were tested in mammalian kidney and osteoblast cells. The results showed that LRP4 suppressed both Wnt/ß-Catenin and Notch signaling pathways, and these activities were perturbed either by LRP4 missense mutations or by a knockdown of LRP4. Our finding underscore that LRP4 is required for limiting Jagged-Notch signaling throughout the fin/limb and kidney development, whose perturbation representing a novel mechanism for LRP4-related diseases. Moreover, our study reveals an evolutionarily conserved relationship between LRP4 and Jagged-Notch signaling, which may shed light on how the Notch signaling is fine-tuned during fin/limb development.