Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin Attenuates Sorafenib-Induced Myocardial Inflammation and Toxicity.

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1ß/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding.

Silicone Breast Implant Injector: A Retooled Breast Augmentation Device.

Silicone breast implants are used worldwide for breast augmentation. After an axillary, periareolar or inframmary incision has been made to create an adequately sized pocket; the surgeon usually uses his or her fingers to insert the implant. The use of fingers makes the insertion process time-consuming, a few minutes or more. There are some complications, including need to ensure that the incision is long enough for the implant to be inserted, scar hypertrophy caused by implant insertion friction damage to the edge of incision, and the occasional need to ask the surgical assistant to lend more fingers to facilitate satisfactory insertion and placement. In addition, the use of gloved fingers to repeatedly push on the implant can increase the risk of contamination, postoperative silicone microleakage, and capsular contracture. To resolve these problems, we developed an improved silicone breast implant injector (reusable stainless steel 2007; single use polypropylene 2018) that can be used more easily than fingers and other "no touch" devices. From 2013 to 2017, the first author, a plastic surgeon at our clinic, used the 2007 reusable stainless steel injector to perform breast augmentations in 53 patients (Ave. age 23.8 years; range 19-67 years), 5 (8.8%) receiving 250-ml implants, 41 (77.4%) 251-300-ml implants, and 7 (13.8%) 301-400-ml implants. Overall, results were satisfactory except for two patients (3.7%) in whom capsular contracture occurred. There were no ruptures. Use of the injector made it possible to shorten the length of the incisions from the traditional 4-7 to 3-4 cm and expedited insertion time from a few minutes to a few seconds. This "no touch" insertion technique reduced implant damage caused by finger pushing, leading to a decrease in silicone microleakage and capsular contracture rate. It was performed with no friction trauma to the incision edge or harm to the surgeon's fingers. It was found to be an effective alternative operative tool for the insertion of silicone breast implants.Level of evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Restoration of HDAC1 Enzymatic Activity after Stroke Protects Neurons from Ischemia/Reperfusion Damage and Attenuates Behavioral Deficits in Rats.

A therapeutic approach for promoting neuroprotection and brain functional regeneration after strokes is still lacking. Histone deacetylase 1 (HDAC1), which belongs to the histone deacetylase family, is involved in the transcriptional repression of cell-cycle-modulated genes and DNA damage repair during neurodegeneration. Our previous data showed that the protein level and enzymatic activity of HDAC1 are deregulated in stroke pathogenesis. A novel compound named 5104434 exhibits efficacy to selectively activate HDAC1 enzymatic function in neurodegeneration, but its potential in stroke therapy is still unknown. In this study, we adopted an induced rat model with cerebral ischemia using the vessel dilator endothelin-1 to evaluate the potential of compound 5104434. Our results indicated compound 5104434 selectively restored HDAC1 enzymatic activity after oxygen and glucose deprivation, preserved neurite morphology, and protected neurons from ischemic damage in vitro. In addition, compound 5104434 attenuated the infarct volume, neuronal loss, apoptosis, DNA damage, and DNA breaks in cerebral ischemia rats. It further ameliorated the behavioral outcomes of neuromuscular response, balance, forepaw strength, and functional recovery. Collectively, our data support the efficacy of compound 5104434 in stroke therapy and contend that it can be considered for clinical trial evaluation.

Velar Closing Ratio As a Predictor for the Verlopharyngeal Function After Double Opposing Z-Plasty for Postpalatoplasty Velopharyngeal Insufficiency in Patients With Cleft Palate.

BACKGROUND: This study was designed to identify the potential predictors of postoperative velopharyngeal function after double opposing Z-plasty (DOZP) for the treatment of velopharyngeal insufficiency (VPI) in patients who had prior palatoplasty for cleft palate. METHODS: This retrospective study reviewed the medical records of consecutive patients who received DOZP for VPI after receiving a prior palatoplasty treating cleft palate between 2004 and 2017. The speech outcome of patient was measured using the Pittsburgh Weighted Speech Scale (PWSS) at 6 months following surgery and determined the outcome suggests velopharyngeal competence (PWSS ≤2) or incompetence (PWSS >2). Stepwise logistic regression was used to identify the variables for the prediction of competent surgical outcome. The specific receiver operating characteristic curves with an area under the curve (AUC) was used to evaluate the predictor related to the surgical outcome as competence. RESULTS: The study included 93 patients. Age, relative velar length, velar lengthening, and closure pattern were not significantly associated with postoperative competence status of the patient. The only variable that predicted a successful surgical outcome was preoperative velar closing ratio. However, the accuracy of velar closing ratio in predicting a competent surgical outcome is only moderate (AUC = 70.37). CONCLUSION: The results of this study showed that preoperative velar closing ratio may predict, with moderate accuracy, a successful surgical outcome in patients with postpalatoplasty VPI who undergo DOZP. Therefore, in patients with a low preoperative velar closing ratio, some alternative surgical methods other than DOZP may be considered to avoid unsatisfactory surgical outcome.

Repair of the Nasal Floor by the Cleft Margin Flap in Bilateral Complete Cleft Lip.

Bilateral complete cleft lip deformity has been the most challenging to plastic surgeons, and lots of methods of repair have been described in the literature. The basic principles are to achieve continuity of the orbicularis oris muscle, a balanced Cupid's bow with nasal ala, and a complete reconstruction of the nasal floor. The last one is, however, easily neglected. A well-reconstructed nasal floor serves as a good support of the nasal cartilage, which minimizes secondary deformity. In addition, a nasal floor with sufficient soft tissue and minimal contracture makes bone grafting easier in the future. The cleft margin flap was first introduced by Tajima in 1983 and used for the nasal floor repair in the unilateral complete cleft lip. The authors have used this technique in bilateral complete cleft lip repair, and from our practice, tension-free repairs of the nasal floors could easily be achieved by the cleft margin flaps. The results were satisfying and no significant scar contracture or deformity of the nasal floor was observed during follow-up. The authors conclude that the cleft margin flaps are viable and alternative choices for the repair of the nasal floors in bilateral complete cleft lip without major complications.

Development of a Dual MOS Electronic Nose/Camera System for Improving Fruit Ripeness Classification.

Electronic nose (E-nose) systems have become popular in food and fruit quality evaluation because of their rapid and repeatable availability and robustness. In this paper, we propose an E-nose system that has potential as a non-destructive system for monitoring variation in the volatile organic compounds produced by fruit during the maturing process. In addition to the E-nose system, we also propose a camera system to monitor the peel color of fruit as another feature for identification. By incorporating E-nose and camera systems together, we propose a non-destructive solution for fruit maturity monitoring. The dual E-nose/camera system presents the best Fisher class separability measure and shows a perfect classification of the four maturity stages of a banana: Unripe, half-ripe, fully ripe, and overripe.

Frontal Hyperostosis in the Patients of Craniosynostosis After Cranial Distraction Osteogenesis.

BACKGROUND: Conventional fronto-orbital advancement and distraction osteogenesis (DOG) have been used to treat craniosynostosis, both of which are considered effective. During the authors' practice, a phenomenon of frontal hyperostosis has been observed in the patients of craniosynostosis after DOG, which has yet to be reported in the literature. The purpose of this study is trying to identify the factors related to the phenomenon. MATERIALS AND METHODS: From 1997 to 2010, all patients of craniosynostosis undergoing DOG were reviewed. The patient's age at operation, consolidation period, numbers of distractor, distance of distraction, and duration from removal of the distractors to identification of the phenomenon on computed tomography were recorded. The phenomenon was considered positive when the hyperostosis appeared on the frontal bone, where it was neither the osteotomy site nor the previous position of distractor. RESULTS: A total of 61 patients were included in this study, including 26 syndromic and 35 nonsyndromic patients. Two syndromic and 6 nonsyndromic patients had the phenomenon. There was no statistical difference between the patients with and without the phenomenon in comparison with the age, number of the distractor, consolidation period, and the distance of distraction. CONCLUSION: Frontal hyperostosis happened in some patients of craniosynostosis after DOG. Although no significant difference was demonstrated, the incidence of hyperostosis was higher in nonsyndromic patients and the patients of hyperostosis had shorter distance of distraction in both syndromic and nonsyndromic groups. Although the definite cause was unknown, we should pay attention to the phenomenon after distraction.

Incidence and excess mortality of hip fracture in young adults: a nationwide population-based cohort study.

BACKGROUND: This study assessed the incidence and excess mortality of hip fractures among inpatients aged 20-40 years in a nationwide population database in Taiwan. METHODS: Subjects were selected from Taiwan's National Health Insurance Research Database for the period 2001-2008 and were followed up until the end of 2010. A total of 4,523 subjects were admitted for the first time with primary diagnosis of hip fracture and treated with operation. RESULTS: The overall annual incidence, mortality, and standardized mortality ratio (SMR) decreased from 7.68 to 7.23 per 100,000, from 1.37 % to 0.94 %, and from 9.06 to 6.71, respectively, from 2001 to 2008. The 1-year, 2-year, 3-year, 5-year, and 10-year mortality rates were 1.28 %, 2.44 %, 3.54 %, 5.32 %, and 10.50 %, respectively for the whole cohort. The 1-year, 2-year, 3-year, 5-year, and 10-year SMRs were 8.33, 7.59, 7.28, 6.39, and 5.82, respectively, for the whole cohort. Risk factors for overall death were male gender, trochanteric fracture, hemiarthroplasty, and higher Charlson comorbidity index (CCI) scores. CONCLUSIONS: The high SMRs found in the present study suggest that young adults with former hip fracture should be closely followed up to prevent early mortality.

A Low Noise CMOS Readout Based on a Polymer-Coated SAW Array for Miniature Electronic Nose.

An electronic nose (E-Nose) is one of the applications for surface acoustic wave (SAW) sensors. In this paper, we present a low-noise complementary metal-oxide-semiconductor (CMOS) readout application-specific integrated circuit (ASIC) based on an SAW sensor array for achieving a miniature E-Nose. The center frequency of the SAW sensors was measured to be approximately 114 MHz. Because of interference between the sensors, we designed a low-noise CMOS frequency readout circuit to enable the SAW sensor to obtain frequency variation. The proposed circuit was fabricated in Taiwan Semiconductor Manufacturing Company (TSMC) 0.18 µm 1P6M CMOS process technology. The total chip size was nearly 1203 × 1203 µm². The chip was operated at a supply voltage of 1 V for a digital circuit and 1.8 V for an analog circuit. The least measurable difference between frequencies was 4 Hz. The detection limit of the system, when estimated using methanol and ethanol, was 0.1 ppm. Their linearity was in the range of 0.1 to 26,000 ppm. The power consumption levels of the analog and digital circuits were 1.742 mW and 761 µW, respectively.

Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.

TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies.

Antimicrobial-impregnated dressing combined with negative-pressure wound therapy increases split-thickness skin graft engraftment: a simple effective technique.

OBJECTIVE: Immobilization and adequate surface contact to wounds are critical for skin graft take. Techniques such as the tie-over dressing, cotton bolster, and vacuum-assisted closure are used to address this, but each has its limitations. This study is designed to assess the effect of antimicrobial-impregnated dressing (AMD) combined with negative-pressure wound therapy (NPWT) on skin graft survival. DESIGN: Retrospective case-control study PARTICIPANTS: : Patients with chronic or contaminated wounds treated with split-thickness skin graft. A broad spectrum of wounds was included, from causes such as trauma, burns, chronic diabetic ulcers, and infection. INTERVENTIONS: Antimicrobial-impregnated dressing, which contains 0.2% polyhexamethylene biguanide, with NPWT MAIN OUTCOME MEASURE:: Success of skin graft MAIN RESULTS: : In the AMD group, all skin grafts achieved 100% take without secondary intervention. No infection or graft failure was observed in any patients, and no complications, such as hematoma or seroma formation, were noted, although in the control group partial loss of skin grafts was noted in 3 patients. Infection and inadequate immobilization were thought to be the main reasons. There were no hematoma or seroma formations in the control group. CONCLUSION: Use of an AMD dressing with NPWT after split-thickness skin grafting can be an effective method to ensure good graft to wound contact and enhances skin graft take in chronic and contaminated wounds.

Mortality and complications of hip fracture in young adults: a nationwide population-based cohort study.

BACKGROUND: This study assessed the mortality and complications of hip fractures using in-patients aged 20-40 years from a nationwide population database in Taiwan. METHODS: Subjects were selected from Taiwan's National Health Insurance Research Database for the period 2000-2008, and these subjects were followed up until the end of 2010. A total of 5,079 (3,879 male and 1,200 female) subjects were admitted for the first time with primary diagnosis of hip fracture and treated with operation. We calculated the long-term overall survival rate and complication-free rate. We also assessed the risk factors for mortality and complications. RESULTS: The 1-month, 3-month, 6-month, 1-year, 2-year, 5-year, and 10-year complication-free rates were 98.3%, 96.2%, 94.5%, 86.8%, 80.4%, 75.3%, and 73.5% for the entire cohort, respectively. The 10-year survival rates were 93.3%, 91.8%, and 94.5% for total cases, trochanteric fracture, and cervical fracture, respectively. The 10-year complication-free rates were 73.5%, 80.5%, and 67.3% for total cases, trochanteric fracture, and cervical fracture, respectively. The risk factors for overall death were male, older age, and greater number of Charlson comorbidity index (CCI) comorbidities. The risk factors for complication were cervical fracture, and greater number of CCI comorbidities. Complications resulted in 42.83% of patients receiving internal fixation implants or prothesis removal and 2.01% underwent conversion to revision arthroplasty during follow-up. CONCLUSIONS: The overall 10-year survival rate in hip fracture patients aged 20-40 years in Taiwan was over 90%. The 10-year complication-free rates were around 70%. Preventing the occurrence of severe complications after hip fracture among young adults is an important public health issue that warrants greater attention.

Free tissue transfers in head and neck reconstruction: complications, outcomes and strategies for management of flap failure: analysis of 2019 flaps in single institute.

BACKGROUND: Free tissue transfer has become the preferred option for complex reconstructions in head and neck cancer ablation. This study reviewed the surgical outcome and analyzed the evolution of microsurgical head and neck reconstruction over 20 years in single institute. PATIENTS AND METHODS: A total of 1,918 patients underwent microsurgical head and neck reconstructions in 20-year period. The surgical outcome and complications among these 2,019 flaps (1,223 anterolateral thigh flaps, 372 fibula flaps, 353 radial forearm flaps, 12 jejunal flaps, and 59 others) were retrospectively reviewed and analyzed. RESULTS: A total of 201 cases required emergent surgical re-exploration and the overall flap success rate was 96.2%. Venous insufficiency was the most common cause for re-exploration. Other major complications included fistula formation (5.4%), partial flap necrosis (7.5%), and infection (17.8%). The fibula flap had frequent complications compared with soft tissue flaps. The familiarity to the ALT flap had minimized complications and allowed for widely versatile uses. CONCLUSION: Free tissue transfer is shown to be highly reliable option for head and neck reconstruction. For soft tissue defect, ALT flap is the first choice. Fibula flap is ideal for bone defect reconstruction. In case of complex composite defects, double flaps, which include ALT and fibula flaps could reconstruct bone and soft tissue defects simultaneously with high success rate.

HDAC1 is Involved in Neuroinflammation and Blood-Brain Barrier Damage in Stroke Pathogenesis.

Background: Stroke is a common cause of disability and mortality worldwide; however, effective therapy remains limited. In stroke pathogenesis, ischemia/reperfusion injury triggers gliosis and neuroinflammation that further activates matrix metalloproteinases (MMPs), thereby damaging the blood-brain barrier (BBB). Increased BBB permeability promotes macrophage infiltration and brain edema, thereby worsening behavioral outcomes and prognosis. Histone deacetylase 1 (HDAC1) is a repressor of epigenomic gene transcription and participates in DNA damage and cell cycle regulation. Although HDAC1 is deregulated after stroke and is involved in neuronal loss and DNA repair, its role in neuroinflammation and BBB damage remains unknown. Methods: The rats with cerebral ischemia were evaluated in behavioral outcomes, levels of inflammation in gliosis and cytokines, and BBB damage by using an endothelin-1-induced rat model with cerebral ischemia/reperfusion injury. Results: The results revealed that HDAC1 dysfunction could promote BBB damage through the destruction of tight junction proteins, such as ZO-1 and occludin, after stroke in rats. HDAC1 inhibition also increased the levels of astrocyte and microglial gliosis, tumor necrosis factor-alpha, interleukin-1 beta, lactate dehydrogenase, and reactive oxygen species, further triggering MMP-2 and MMP-9 activity. Moreover, modified neurological severity scores for the cylinder test revealed that HDAC1 inhibition deteriorated behavioral outcomes in rats with cerebral ischemia. Discussion: HDAC1 plays a crucial role in ischemia/reperfusion-induced neuroinflammation and BBB damage, thus indicating its potential as a therapeutic target.

Risk factors for pressure ulcer recurrence following surgical reconstruction: A cross-sectional retrospective analysis.

Many studies on the recurrence of pressure ulcers after surgical reconstruction have focused on surgical techniques and socioeconomic factors. Herein, we aimed to identify the risk factors of the associated comorbidities for pressure ulcer recurrence. We enrolled 147 patients who underwent pressure ulcer reconstruction and were followed up for more than three years. The recurrence of pressure ulcers was defined as recurrent pressure ulcers with stage 3/4 pressure ulcers. We reviewed and analyzed systematic records of medical histories, including sex, age, associated comorbidities such as spinal cord injury (SCI), diabetes mellitus (DM), coronary artery disease, cerebral vascular accident, end-stage renal disease, scoliosis, dementia, Parkinson's disease, psychosis, autoimmune diseases, hip surgery, and locations of the primary pressure ulcer. Patients with recurrent pressure ulcers were younger than those without. Patients with SCI and scoliosis had higher odds, while those with Parkinson's disease had lower odds of recurrence of pressure ulcers than those without these comorbidities. Moreover, the decision tree algorithm identified that SCI, DM, and age < 34 years could be risk factor classifiers for predicting recurrent pressure ulcers. This study demonstrated that age and SCI are the two most important risk factors associated with recurrent pressure ulcers following surgical reconstruction.

Direct Effects of Mifepristone on Mice Embryogenesis: An In Vitro Evaluation by Single-Embryo RNA Sequencing Analysis.

The clinical use of mifepristone for medical abortions has been established in 1987 in France and since 2000 in the United States. Mifepristone has a limited medical period that lasts <9 weeks of gestation, and the incidence of mifepristone treatment failure increases with gestation time. Mifepristone functions as an antagonist for progesterone and glucocorticoid receptors. Studies have confirmed that mifepristone treatments can directly contribute to endometrium disability by interfering with the endometrial receptivity of the embryo, thus causing decidual endometrial degeneration. However, whether mifepristone efficacy directly affects embryo survival and growth is still an open question. Some women choose to continue their pregnancy after mifepristone treatment fails, and some women express regret and seek medically unapproved mifepristone antagonization with high doses of progesterone. These unapproved treatments raise the potential risk of embryonic fatality and developmental anomalies. Accordingly, in the present study, we collected mouse blastocysts ex vivo and treated implanted blastocysts with mifepristone for 24 h. The embryos were further cultured to day 8 in vitro to finish their growth in the early somite stage, and the embryos were then collected for RNA sequencing (control n = 3, mifepristone n = 3). When we performed a gene set enrichment analysis, our data indicated that mifepristone treatment considerably altered the cellular pathways of embryos in terms of viability, proliferation, and development. The data indicated that mifepristone was involved in hallmark gene sets of protein secretion, mTORC1, fatty acid metabolism, IL-2-STAT5 signaling, adipogenesis, peroxisome, glycolysis, E2F targets, and heme metabolism. The data further revealed that mifepristone interfered with normal embryonic development. In sum, our data suggest that continuing a pregnancy after mifepristone treatment fails is inappropriate and infeasible. The results of our study reveal a high risk of fetus fatality and developmental problems when pregnancies are continued after mifepristone treatment fails.

Impaired Ventrolateral Periaqueductal Gray-Ventral Tegmental area Pathway Contributes to Chronic Pain-Induced Depression-Like Behavior in Mice.

Chronic pain conditions within clinical populations are correlated with a high incidence of depression, and researchers have reported their high rate of comorbidity. Clinically, chronic pain worsens the prevalence of depression, and depression increases the risk of chronic pain. Individuals suffering from chronic pain and depression respond poorly to available medications, and the mechanisms underlying the comorbidity of chronic pain and depression remain unknown. We used spinal nerve ligation (SNL) in a mouse model to induce comorbid pain and depression. We combined behavioral tests, electrophysiological recordings, pharmacological manipulation, and chemogenetic approaches to investigate the neurocircuitry mechanisms of comorbid pain and depression. SNL elicited tactile hypersensitivity and depression-like behavior, accompanied by increased and decreased glutamatergic transmission in dorsal horn neurons and midbrain ventrolateral periaqueductal gray (vlPAG) neurons, respectively. Intrathecal injection of lidocaine, a sodium channel blocker, and gabapentin ameliorated SNL-induced tactile hypersensitivity and neuroplastic changes in the dorsal horn but not depression-like behavior and neuroplastic alterations in the vlPAG. Pharmacological lesion of vlPAG glutamatergic neurons induced tactile hypersensitivity and depression-like behavior. Chemogenetic activation of the vlPAG-rostral ventromedial medulla (RVM) pathway ameliorated SNL-induced tactile hypersensitivity but not SNL-elicited depression-like behavior. However, chemogenetic activation of the vlPAG-ventral tegmental area (VTA) pathway alleviated SNL-produced depression-like behavior but not SNL-induced tactile hypersensitivity. Our study demonstrated that the underlying mechanisms of comorbidity in which the vlPAG acts as a gating hub for transferring pain to depression. Tactile hypersensitivity could be attributed to dysfunction of the vlPAG-RVM pathway, while impairment of the vlPAG-VTA pathway contributed to depression-like behavior.

Slow skeletal muscle troponin T acts as a potential prognostic biomarker and therapeutic target for hepatocellular carcinoma.

Slow skeletal muscle troponin T (TNNT1) as a poor prognostic indicator is upregulated in colon and breast cancers. However, the role of TNNT1 in the disease prognosis and biological functions of hepatocellular carcinoma (HCC) is still unclear. The Cancer Genome Atlas (TCGA), real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to evaluate the TNNT1 expression of human HCC. The impact of TNNT1 levels on disease progression and survival outcome was studied using TCGA analysis. Moreover, the bioinformatics analysis and HCC cell culture were used to investigate the biological functions of TNNT1. Besides, the immunoblot analysis and enzyme-linked immunosorbent assay (ELISA) were used to detect the extracellular TNNT1 of HCC cells and circulating TNNT1 of HCC patients, respectively. The effect of TNNT1 neutralization on oncogenic behaviors and signaling was further validated in the cultured hepatoma cells. In this study, tumoral and blood TNNT1 was upregulated in HCC patients based on the analyses using bioinformatics, fresh tissues, paraffin sections, and serum. From the multiple bioinformatics tools, the TNNT1 overexpression was associated with advanced stage, high grade, metastasis, vascular invasion, recurrence, and poor survival outcome in HCC patients. By the cell culture and TCGA analyses, TNNT1 expression and release were positively correlated with epithelial-mesenchymal transition (EMT) processes in HCC tissues and cells. Moreover, TNNT1 neutralization suppressed oncogenic behaviors and EMT in hepatoma cells. In conclusion, TNNT1 may serve as a non-invasive biomarker and drug target for HCC management. This research finding may provide a new insight for HCC diagnosis and treatment.

Long-term DEHP/MEHP exposure promotes colorectal cancer stemness associated with glycosylation alterations.

Plasticizers are considered as environmental pollution released from medical devices and increased potential oncogenic risks in clinical therapy. Our previous studies have shown that long-term exposure to di-ethylhexyl phthalate (DEHP)/mono-ethylhexyl phthalate (MEHP) promotes chemotherapeutic drug resistance in colorectal cancer. In this study, we investigated the alteration of glycosylation in colorectal cancer following long-term plasticizers exposure. First, we determined the profiles of cell surface N-glycomes by using mass spectrometry and found out the alterations of α2,8-linkages glycans. Next, we analyzed the correlation between serum DEHP/MEHP levels and ST8SIA6 expression from matched tissues in total 110 colorectal cancer patients. Moreover, clinical specimens and TCGA database were used to analyze the expression of ST8SIA6 in advanced stage of cancer. Finally, we showed that ST8SIA6 regulated stemness in vitro and in vivo. Our results revealed long-term DEHP/MEHP exposure significantly caused cancer patients with poorer survival outcome and attenuated the expression of ST8SIA6 in cancer cells and tissue samples. As expected, silencing of ST8SIA6 promoted cancer stemness and tumorigenicity by upregulating stemness-associated proteins. In addition, the cell viability assay showed enhanced drug resistance in ST8SIA6 silencing cells treated with irinotecan. Besides, ST8SIA6 was downregulated in the advanced stage and positively correlated with tumor recurrence in colorectal cancer. Our results imply that ST8SIA6 potentially plays an important role in oncogenic effects with long-term phthalates exposure.

TDP-43 regulates the mammalian spinogenesis through translational repression of Rac1.

Impairment of learning and memory is a significant pathological feature of many neurodegenerative diseases including FTLD-TDP. Appropriate regulation and fine tuning of spinogenesis of the dendrites, which is an integral part of the learning/memory program of the mammalian brain, are essential for the normal function of the hippocampal neurons. TDP-43 is a nucleic acid-binding protein implicated in multi-cellular functions and in the pathogenesis of a range of neurodegenerative diseases including FTLD-TDP and ALS. We have combined the use of single-cell dye injection, shRNA knockdown, plasmid rescue, immunofluorescence staining, Western blot analysis and patch clamp electrophysiological measurement of primary mouse hippocampal neurons in culture to study the functional role of TDP-43 in mammalian spinogenesis. We found that depletion of TDP-43 leads to an increase in the number of protrusions/spines as well as the percentage of matured spines among the protrusions. Significantly, the knockdown of TDP-43 also increases the level of Rac1 and its activated form GTP-Rac1, a known positive regulator of spinogenesis. Clustering of the AMPA receptors on the dendritic surface and neuronal firing are also induced by depletion of TDP-43. Furthermore, use of an inhibitor of Rac1 activation negatively regulated spinogenesis of control hippocampal neurons as well as TDP-43-depleted hippocampal neurons. Mechanistically, RT-PCR assay and cycloheximide chase experiments have indicated that increases in Rac1 protein upon TDP-43 depletion is regulated at the translational level. These data together establish that TDP-43 is an upstream regulator of spinogenesis in part through its action on the Rac1 â†’ GTP-Rac1 â†’ AMPAR pathway. This study provides the first evidence connecting TDP-43 with the GTP-Rac1 â†’ AMPAR regulatory pathway of spinogenesis. It establishes that mis-metabolism of TDP-43, as occurs in neurodegenerative diseases with TDP-43 proteinopathies, e.g., FTLD-TDP, would alter its homeostatic cellular concentration, thus leading to impairment of hippocampal plasticity.