A novel HDAC6 inhibitor interferes microtubule dynamics and spindle assembly checkpoint and sensitizes cisplatin-induced apoptosis in castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (CRPC), the most refractory prostate cancer, inevitably progresses and becomes unresponsive to hormone therapy, revealing a pressing unmet need for this disease. Novel agents targeting HDAC6 and microtubule dynamics can be a potential anti-CRPC strategy. METHODS: Cell proliferation was examined in CRPC PC-3 and DU-145 cells using sulforhodamine B assay and anchorage-dependent colony formation assay. Flow cytometric analysis of propidium iodide staining was used to determine cell-cycle progression. Cell-based tubulin polymerization assay and confocal immunofluorescence microscopic examination determine microtubule assembly/disassembly status. Protein expressions were determined using Western blot analysis. RESULTS: A total of 82 novel derivatives targeting HDAC6 were designed and synthesized, and Compound 25202 stood out, showing the highest efficacy in blocking HDAC6 (IC50, 3.5 nM in enzyme assay; IC50, 1.0 µM in antiproliferative assay in CRPC cells), superior to tubastatin A (IC50, 5.4 µM in antiproliferative assay). The selectivity and superiority of 25202 were validated by examining the acetylation of both α-tubulin and histone H3, detecting cell apoptosis and HDACs enzyme activity assessment. Notably, 25202 but not tubastatin A significantly decreased HDAC6 protein expression. 25202 prolonged mitotic arrest through the detection of cyclin B1 upregulation, Cdk1 activation, mitotic phosphoprotein levels, and Bcl-2 phosphorylation. Compound 25202 did not mimic docetaxel in inducing tubulin polymerization but disrupted microtubule organization. Compound 25202 also increased the phosphorylation of CDC20, BUB1, and BUBR1, indicating the activation of the spindle assembly checkpoint (SAC). Moreover, 25202 profoundly sensitized cisplatin-induced cell death through impairment of cisplatin-evoked DNA damage response and DNA repair in both ATR-Chk1 and ATM-Chk2 pathways. CONCLUSION: The data suggest that 25202 is a novel selective and potent HDAC6 inhibitor. Compound 25202 blocks HDAC6 activity and interferes microtubule dynamics, leading to SAC activation and mitotic arrest prolongation that eventually cause apoptosis of CRPC cells. Furthermore, 25202 sensitizes cisplatin-induced cell apoptosis through impeding DNA damage repair pathways.

Consumption of Soya Isoflavones Improved Polycystic Ovary Syndrome (PCOS)-Associated Metabolic Disorders in a Rat Model.

Polycystic ovary syndrome (PCOS) is associated with increased risks for certain metabolic disorders such as insulin resistance, non-alcoholic fatty liver disease (NAFLD), and suppressed ovarian follicular development. This study aimed to examine whether soya isoflavones (ISF) mitigate these PCOS-associated metabolic disorders in a rat model. Weanling Sprague-Dawley female rats were randomly divided into 6 groups and were treated with either 0 or 83 µg/day dihydrotestosterone (DHT) to induce PCOS and fed diets containing 0, 0.5, or 1g ISF/kg diet for 8 weeks. DHT treatment increased food intake, body weight gain (BWG, p<0.001), percentage of primordial follicles (60% vs 50.9%, p<0.05), and accumulation of lipid droplets in the livers. It also elevated serum total cholesterol (TC), free cholesterol (FC), triglycerides, non-esterified fatty acids (NEFA), and leptin, and hepatic TC and NEFA. Additionally, DHT treatment reduced the percentage of primary follicles (13.8% vs 30.2%, p<0.05), ovary weight, and length (p<0.001), as well as insulin sensitivity (p<0.01) compared to the Control. ISF intake at 1g/kg reduced BWG, serum TC, FC, NEFA, leptin, and hepatic triglycerides and DHT-induced insulin resistance (p<0.01). ISF intake at both levels decreased DHT-induced lipid droplet accumulation in the livers, and changes in the percentages of primordial and primary follicles. Dietary soya ISF alleviated DHT-induced BWG, insulin resistance, and hepatic lipid droplet accumulation, as well as suppressed ovarian follicular development. This suggests that consumption of soya foods or ISF supplements may be beneficial for the individuals with PCOS, mitigating the associated metabolic disorders such as diabetes and NAFLD.

Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer.

A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound 3b, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC50 = 16 nM and 1.03 µM, respectively). Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM). Moreover, 3b inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers in vivo, 3b was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.

A network analysis bridging the gap between the big five personality traits and burnout among medical staff.

BACKGROUND: Burnout is a common issue among medical professionals, and one of the well-studied predisposing factors is the Big Five personality traits. However, no studies have explored the relationships between these traits and burnout from a trait-to-component perspective. To understand the specific connections between each Big Five trait and burnout components, as well as the bridging effects of each trait on burnout, we employed network analysis. METHODS: A cluster sampling method was used to select a total of 420 Chinese medical personnel. The 15-item Chinese Big Five Personality Inventory-15 (CBF-PI-15) assessed the Big Five personality traits, while the 15-item Maslach Burnout Inventory-General Survey (MBI-GS) assessed burnout components. Network analysis was used to estimate network structure of Big Five personality traits and burnout components and calculate the bridge expected influence. RESULTS: The study revealed distinct and clear relationships between the Big Five personality traits and burnout components. For instance, Neuroticism was positively related to Doubt significance and Worthwhile, while Conscientiousness was negatively related to Accomplish all tasks. Among the Big Five traits, Neuroticism displayed the highest positive bridge expected influence, while Conscientiousness displayed the highest negative bridge expected influence. CONCLUSIONS: The network model provides a means to investigate the connections between the Big Five personality traits and burnout components among medical professionals. This study offers new avenues for thought and potential targets for burnout prevention and treatment in medical personnel, which can be further explored and tested in clinical settings.

Antagonizing pathological α-synuclein-mediated neurodegeneration by J24335 via the activation of immunoproteasome.

The aggregation of misfolded proteins, such as α-synuclein in Parkinson's disease (PD), occurs intracellularly or extracellularly in the majority of neurodegenerative diseases. The immunoproteasome has more potent chymotrypsin-like activity than normal proteasome. Thus, degradation of α-synuclein aggregation via immunoproteasome is an attractive approach for PD drug development. Herein, we aimed to determine if novel compound, 11-Hydroxy-1-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-1-one oxime (named as J24335), is a promising candidate for disease-modifying therapy to prevent the pathological progression of neurodegenerative diseases, such as PD. The effects of J24335 on inducible PC12/A53T-α-syn cell viability and cytotoxicity were evaluated by MTT assay and LDH assay, respectively. Evaluation of various proteasome activities was done by measuring the luminescence of enzymatic activity after the addition of different amounts of aminoluciferin. Immunoblotting and real-time PCR were employed to detect the expression of various proteins and genes, respectively. We also used a transgenic mouse model for behavioral testing and immunochemical analysis, to assess the neuroprotective effects of J24335. J24335 inhibited wild-type and mutant α-synuclein aggregation without affecting the growth or death of neuronal cells. The inhibition of α-synuclein aggregation by J24335 was caused by activation of immunoproteasome, as mediated by upregulation of LMP7, and increased cellular chymotrypsin-like activity in 20S proteasome. J24335-enhanced immunoproteasome activity was mediated by PKA/Akt/mTOR pathway activation. Moreover, animal studies revealed that J24335 treatment markedly mitigated both the loss of tyrosine hydroxylase-positive (TH-) neurons and impaired motor skill development. This is the first report to use J24335 as an immunoproteasome enhancing agent to antagonize pathological α-synuclein-mediated neurodegeneration.

Transoral endoscopic and robotic thyroidectomy for thyroid cancer: the mid-term oncological outcome.

BACKGROUND: Traditional open thyroidectomy is the surgical standard for thyroid cancer; however, it inevitably leaves a visible scar on the neck and affects the patient's quality of life. Therefore, to avoid making a neck incision, the transoral endoscopic thyroidectomy vestibular approach (TOETVA) and transoral robotic thyroidectomy (TORT) have been developed recently, and the surgical outcomes of these techniques are as favorable as open surgery for benign disease. Additionally, positive short-term surgical outcomes have also been achieved in a few patients with thyroid cancer. However, no data on the mid-to-long-term recurrence and survival rates of transoral thyroidectomy in thyroid cancer are available. Therefore, in this study, we analyzed the surgical outcomes and mid-term oncological results of the TOETVA and TORT in patients with thyroid cancer. METHODS: We reviewed patients who had received TOETVA or TORT between July 2017 and November 2021 and followed up on their oncological outcomes until December 2022. Perioperative surgical and mid-term oncological outcomes were analyzed. RESULTS: The 115 patients underwent 122 operations (57 TOETVAs and 65 TORTs), including seven complete thyroidectomies for differentiated thyroid cancer (DTC), Stage I-II, including T1-T3, N0-N1a, and initial low- to high-risk groups. There was no conversion from transoral to open surgery. TORT required a longer operating time (median [interquartile range]) than TOETVA (lobectomy: 279 [250, 318] vs. 196 [173, 253] min, p < 0.001; bilateral total thyroidectomy: 375 [309, 433] vs. 279 [238, 312] min, p < 0.001); however, no difference was found between the two groups regarding perioperative complications. Complete thyroidectomy with a second transoral approach was safe. TOETVA and TORT achieved favorable oncological outcomes with 100% survival and 98.2% acceptable response (excellent and indeterminate response) during a mean 37.88 ± 12.42 months mid-term follow-up. CONCLUSIONS: Transoral endoscopic and robotic thyroidectomy was safe and achieved favorable mid-term oncological outcomes in a selected cohort of patients with early-stage DTC.

Laparoscopic vs. open feeding jejunostomy: a systemic review and meta-analysis.

BACKGROUND: Feeding jejunostomy is a solid way for patients to maintain enteral nutrition. However, debate over the superiority of the laparoscopic vs. laparotomic method has raised concerns in recent years. This systemic review and meta-analysis aimed to compare the postoperative outcomes between these two approaches. METHODS: We searched PubMed, Embase, and Scopus from the date of inception to April 2022 for studies comparing laparoscopic and open feeding jejunostomy. Study characteristics and outcomes were extracted from the included articles. The primary outcome was the relative risk (RR) of postoperative complications in each group. We also analyzed the major/minor complication rates and operations, excluding major concomitant procedures. The risk of bias of included studies were assessed using the ROBINS-I tool. The certainty of evidence was rated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: A total of seven retrospective studies with 1195 patients in total were included in this systemic review and meta-analysis. Laparoscopic feeding jejunostomy carried a significantly lower postoperative complication rate (RR: 0.62; 95% CI, 0.42-0.91, p = 0.02, low certainty of evidence) compared with laparotomy, and the heterogeneity was moderate (I2 = 34%, p = 0.18). After excluding major concomitant procedures, the RR between the laparoscopic and open group was 0.48 (95% CI, 0.33-0.70, p < 0.001, low certainty of evidence), suggesting that the laparoscopic approach was superior in terms of postoperative complications. CONCLUSIONS: Our results indicate that laparoscopic feeding jejunostomy might reduce the postoperative overall complication rate compared with open feeding jejunostomy.

Digital measurement and clinical significance of proximal femur in the older people of Inner Mongolia population, China.

OBJECTIVE: This study aimed to measure the parameters of the proximal femur in the older people of Inner Mongolia, China and understand the influence of age and gender so as to provide guidance for the design and improvement of prosthesis for total hip arthroplasty. METHODS: A total of 236 patients who underwent CT angiography of lower limbs in the Department of Imaging, Affiliated Hospital of Inner Mongolia Medical University of China were collected. They were divided into 4 groups according to age: < 60 (group A), 60-69 (group B), 70-79 (group C), and > 80 years (group D). Four anatomical parameters, including femoral head diameter (FHD), femoral neck-shaft angle (FNSA), femoral offset (FO), femoral neck anteversion (FNA), were measured by Mimics 21.0. Comparisons were made between age groups of the same gender and between genders in the same age group to analyze the correlation of the 4 parameters of proximal femur with age and gender. In addition, the results of this study were compared with previous studies. RESULTS: There were no significant differences in FHD and FO between age groups, indicating no correlation with age. FNSA and FNA were no significantly different between group C and group D in the same gender, whereas there were significant differences between other age groups and were negatively correlated with age. There were significant differences in FHD and FO between genders in the same age group, with the males being larger than the females. FNSA and FNA were no significant differences between genders in the same age group. CONCLUSIONS: FNSA and FNA decrease with age. FHD and FO were larger in males than in females in all age groups. Age and gender should be considered in the design of prosthesis.

Study on anti-inflammatory effect of peptides-conjugated alumina nanoparticle on allergic rhinitis mice model.

Allergic rhinitis (AR) is a common atopic problem in which immune response to the environmental factors leads to clinical symptoms. Helicobacter pylori neutrophil-activating protein (HP-NAP) as a peptide attenuates Th2 response and stimulates Th1 activation and mucus adhesion promoting protein (MapA) as a cell-surface protein binds to mucus. This study evaluated the effect of HP-NAP and MapA conjugated with alumina nanoparticle on AR. HP-NAP and HP-NAP with MapA were conjugated to alumina nanoparticle and two separate nanoparticles were produced. The AR mice were treated with these and HP-NAP in peptide form. The AR symptoms, gene expression of mucus, levels of IL-33 and IL-4, and total and ovalbumin (OVA)-specific IgE levels were evaluated. Nasal rubbing, sneezing, gene expression of mucus, and IL-33 and IL-4 levels, and OVA-specific and total IgE were decreased in three treated groups compared to AR, and there was a significant decrease in the symptoms in AR-H-M-A group (P < 0.05) when compared to the other treated groups. HP-NAP has a controlling effect on AR, and in nanoparticle-conjugated form it can strongly attach to the airway's mucus via MapA. Therefore, cooperation of HP-NAP-alumina with MapA can produce an effective and applicable treatment for AR.

Nursing teachers' job burnout and teaching ability: The mediating role of social support based on the Person-Context interaction theory.

BACKGROUND: Great attention has been attached to the quality of nursing along with the development of medical treatment, which gives rise to the higher demand for colleges to cultivate high-quality nursing students, as well as the higher standard for teaching performance of the nursing faculty. OBJECTIVE: This study aimed to investigate the effect of teachers' job burnout on teaching ability among nursing teachers in Chinese colleges and to examine the mediating role of social support in this relationship based on the Person-context interaction theory. DESIGN: A cross-sectional descriptive design has been adopted. METHODS: From February to June 2021, a total of 416 Chinese nursing teachers from 27 colleges filled out the questionnaires with a response rate of 97.42%. The questionnaire included general demographic questionnaire, teaching ability in nursing scale, teacher burnout scale and social support scale. The data were analyzed by SPSS26.0 statistical software in terms of Pearson's correlation the Structural Equation Model (SEM) was adopted to test the mediating effect of social support between job burnout and teaching ability in nursing of nursing teachers using Mplus 8.3. RESULTS: Job burnout of nursing teachers was negatively and significantly correlated with the teaching ability in nursing and social support (p < 0.01). And Structural Equation Model results showed that social support mediated the relationship between teacher burnout and teaching ability in nursing. CONCLUSIONS: Social support could help nursing teachers manage their job burnout, and eventually help them overcome the negative impact of teachers' job burnout on teaching ability in nursing. Social support could promote the teaching ability of nursing teachers by playing an intermediary role between them.[Box: see text].

Should we change the treatment plan in early hepatocellular carcinoma with chronic kidney disease?

BACKGROUND: Chronic kidney disease (CKD) has been considered to be a poor prognostic factor for hepatocellular carcinoma (HCC). However, few studies have focused on early HCC and the impact of CKD on survival, which should be considered in curative treatment for early HCC. MATERIALS AND METHODS: Patients with BCLC stage 0/A were enrolled from 2009 to 2019. A total of 383 patients were divided into Control group and CKD group, based on estimated glomerular filtration rate. Overall survival (OS) and disease-free survival (DFS) of different treatments were determined using the Kaplan-Meier method. RESULTS: The Control group had a significantly better OS than the CKD group (72.6 months vs. 56.7 months; p = 0.003). DFS was similar between the groups (62.2 months vs. 63.8 months, p = 0.717). In the Control group, the surgically treated (OP) group had significantly superior OS (65.0 months vs. 80.0 months, p = 0.014) and DFS (50.9 months vs. 70.2 months, p = 0.020) than the radiofrequency ablation-treated group. In the CKD group, the OP group showed a survival advantage in OS (70.6 months vs. 49.2 months, p = 0.004), while DFS was similar between treatment groups (56.0 months vs. 62.2 months, p = 0.097). CONCLUSION: CKD should not be considered to be a poor prognostic factor in early HCC patients. Moreover, hepatectomy should be carried out in CKD patient with early HCC for better prognosis if feasible.

Spatial-temporal Distribution and Influencing Factors of Helicobacter pylori Infection in Chinese Mainland, 2001-2020: A Systematic Review and Meta-Analysis.

BACKGROUND: The spatial-temporal distribution of Helicobacter pylori infection in China is poorly understood. We aimed to study the spatial-temporal distribution of H. pylori infection in Chinese mainland and to explore its influencing factors. MATERIALS AND METHODS: We searched the relevant literature from 2001 to 2021 and applied meta-analysis to obtain the pooled prevalence estimates of all studies and subgroups. Then, we used the pooled prevalence as the dependent variable for the following analysis, including time series analysis, statistical mapping, spatial autocorrelation analysis, and influencing factor analysis based on generalized additive model and panel data model. RESULTS: A total of 726 articles and 3,407,392 people were included. The pooled prevalence was 43.7% (95% confidence interval: 42.7%-44.8%). The prevalence decreased in the past 20 years, with high in the eastern and western regions and low in the central region. Qinghai Tibet Plateau and Guizhou Plateau were the high incidence areas of this disease. The intake of vegetable oil, aquatic products, meat, milk, per capita gross domestic product, and annual average humidity were significantly correlated with H. pylori. CONCLUSIONS: The prevalence of H. pylori is decreasing in Chinese mainland, but still high in underdeveloped areas. Appropriate strategies for the prevention need greater attention.

Hypolipidemic Effects of Soy Protein and Isoflavones in the Prevention of Non-Alcoholic Fatty Liver Disease- A Review.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and affects about 25% of the population globally. Obesity and diabetes are the main causes of the disease characterized by excessive accumulation of lipids in the liver. There is currently no direct pharmacological treatments for NAFLD. Dietary intervention and lifestyle modification are the key strategies in the prevention and treatment of the disease. Soy consumption is associated with many health benefits such as decreased incidence of coronary heart disease, type-2 diabetes, atherosclerosis and obesity. The hypolipidemic functions of soy components have been shown in both animal studies and human clinical trials. Dietary soy proteins and associated isoflavones suppressed the formation and accumulation of lipid droplets in the liver and improved NAFLD-associated metabolic syndrome. The molecular mechanism(s) underlying the effects of soy components are mainly through modulation of transcription factors, sterol regulatory element-binding protein-1 and peroxisome proliferator-activated receptor-γ2, and expressions of their target genes involved in lipogenesis and lipolysis as well as lipid droplet-promoting protein, fat-specific protein-27. Inclusion of appropriate amounts of soy protein and isoflavones in the diets might be a useful approach to decrease the prevalence of NAFLD and mitigate disease burden.

Effects of dietary active soybean trypsin inhibitors on pancreatic weights, histology and expression of STAT3 and receptors for androgen and estrogen in different tissues of rats.

Our previous study showed that soy milks could contain high levels of active soybean trypsin inhibitors (SBTI) if they were not properly processed. This study investigated the effects of consuming active SBTI on pancreatic weights, histology, trypsinogen production and expression of STAT3, receptors for androgen (AR) and estrogen (ER) in pancreas, liver and uterus of rats. Weanling Sprague-Dawley rats were randomly divided into 3 groups (8 females and 8 males/group) and fed diets containing either 20% casein protein (Casein) or 20% soy protein (SP) in the presence of high (1.42 BAEE unit/µg, SP + SBTI) or low (0.2 BAEE unit/µg, SP-SBTI) levels of active SBTI for 8 weeks. Ingestion of SP + SBTI diet markedly increased pancreatic weights and trypsinogen content (p < 0.01), and caused acinar cell hypertrophy, and reduced pancreatic STAT3, p-STAT3, AR and ERß content, and increased uterine ERα and ERß compared to the Casein or SP-SBTI diets (p < 0.05). The two SP-containing diets lowered hepatic STAT3, p-STAT3, and pancreatic ERα, and increased hepatic ERα and ERß content in the female rats compared to the Casein diet (p < 0.05). This study demonstrated for the first time that consumption of high level of active SBTI not only increased pancreatic weights and acinar cell secretions, but also attenuated the expression of pancreatic STAT3, p-STAT3, AR, and ERß proteins in both sexes and increased uterine ERα and ERß content, and that dietary soy protein affected hepatic STAT3, p-STAT3, ERα and ERß in a gender-dependent manner.

Inhibitor development of MTH1 via high-throughput screening with fragment based library and MTH1 substrate binding cavity.

MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC50 inhibition abilities by enzyme kinetics and Kd values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.

Distant Intramuscular Metastases of Head and Neck Squamous Cell Carcinoma.

OBJECTIVES: Metastasis of head and neck squamous cell carcinoma (HNSCC) usually occurs regionally in the neck lymph nodes, but also more infrequently at distant organs (eg, the lungs, bone, and liver). Intramuscular metastasis (IMM) has rarely been described. Therefore, we aimed to identify this disease characteristic and to evaluate available medical management options. METHODS: Data of surgically treated HNSCC patients (n = 1150) at the Chi Mei Medical Center, Taiwan (2005-2015), were retrospectively reviewed. Literature searches were also conducted (1985-2015) to analyze the behavior of HNSCC with distant IMMs. RESULTS: We identified 1 HNSCC patient with histopathologically proven IMMs. Ten similar cases were also identified in the available literature. Two-thirds of lesions arose in patients with laryngeal/hypopharyngeal malignancies, and two-thirds of lesions were located in the lower limbs. Lesions were subjectively painful and usually had rim enhancement with central hypoattenuation in contrast-enhanced computed tomography/magnetic resonance imaging. The mean duration between primary tumor diagnosis and secondary lesion detection was 13.7 months. No patient survived more than 2 years after establishing a diagnosis of HNSCC with IMMs. CONCLUSIONS: Distant IMMs are extremely rare in HNSCC patients and have a poor clinical outcome. Differentiating this disease from sarcoma via anatomic distribution or diagnostic imaging studies is not straightforward. Biopsies for histopathologic examination are mandatory. Treatment of HNSCC patients with IMMs is mainly palliative for life quality preservation and not lifetime prolongation. Radiotherapy is established as a first-line treatment for symptom control with surgical intervention usually preserved for refractory cases.

Dietary supplementation with L-lysine affects body weight and blood hematological and biochemical parameters in rats.

L-Lysine (Lys) is a popular additive in foods, but the physiological effects of excess Lys supplementation are poorly understood and upper limits of safe intake have not been established. The objectives of this study were to examine the effects of dietary supplementation with increasing amounts of Lys on body weight (BW), food intake, and various blood hematological and biochemical parameters in rats. Male Sprague-Dawley rats at 10 weeks of age were assigned to ten diet groups (eight rats/group) and fed diets containing either 7% or 20% casein and supplemented with either 0% (Control), 1.5%, 3%, 6% Lys, or 6% Lys + 3% arginine for 1 week. Rats fed 7% casein with ≥ 1.5% Lys supplementation had lower serum albumin and leptin and higher LDL cholesterol (LDLC), ratios of total cholesterol (TC):HDL cholesterol (HDLC) and LDLC:HDLC than those fed 7% casein Control diet (P < 0.05). Rats fed 7% casein diet supplemented with 3% Lys diet had lower BW gain, food intake, serum alkaline phosphatase activity, and increased mean corpuscular hemoglobin concentration, blood urea nitrogen and serum pancreatic polypeptide compared to rats fed the Control diet (P < 0.05). Addition of 6% Lys in 7% casein caused significant BW loss (P < 0.001) and altered additional parameters. Addition of 6% Lys in a 20% casein diet reduced BW gain and food intake and altered numerous parameters. Arg supplementation normalized many of the endpoints changed by Lys. Collectively, these results show that Lys supplementation affects BW, food intake and a number of hematological and biochemical parameters. These effects of Lys supplementation were confined primarily in diets with lower levels of dietary protein. In the context of a low protein diet (7% casein), levels of Lys supplementation ≥ 1.5% may exert adverse health effects in rats.

Dietary L-lysine supplementation altered the content of pancreatic polypeptide, enzymes involved in glutamine metabolism, and ß-actin in rats.

This study investigated the effects of Lys supplementation on serum pancreatic polypeptide (PP), glutamine (Gln) levels and the expression of PP, Gln synthetase (GlnS), glutaminase (Gls) and ß-actin in different tissues such as pancreas, skeletal muscle, liver and kidney in rats. Male Sprague-Dawley rats were fed diets containing 7% casein supplemented with either 0% (Control), 1%, 1.5%, 3% Lys or 3% Lys with 1.5% Arg for a week. All rats were necropsied for collection of blood and tissues. Expression of PP, GlnS, Gls, and ß-actin in tissues were determined using Western blotting. The results showed that the rats fed 3% supplemental Lys had significantly lower body weight gain (BWG) and food intake than the ≤ 1.5% Lys groups (P < 0.05). Supplementation with ≥ 1% Lys increased serum PP level (P < 0.05), but had no significant effect on pancreatic PP abundance (P > 0.05). GlnS expression was significantly lowered in skeletal muscle by ≥ 1.5% supplemental Lys compared to the Control (P < 0.05). The expression of Gls in the kidney was increased by the addition of 1.5% Arg to 3% Lys diet (P < 0.05). Liver ß-actin significantly increased with both Lys and Arg supplementation and muscle ß-actin significantly decreased (P < 0.05) with ≥ 1.5% supplemental Lys. Kidney ß-actin significantly increased with Arg supplementation vs 3% Lys alone (P < 0.05). These results showed that dietary supplementation with ≥ 1.5% Lys significantly suppressed GlnS expression in the skeletal muscle, which may contribute to the decreased serum Gln levels, and that increased serum PP by Lys may be due to suppressed catabolism rather than increased synthesis of PP. Lys-induced PP may play a role in reducing food intake and BWG.

A highly HDAC6-selective inhibitor acts as a fluorescent probe.

HDAC6 receives great attention because of its therapeutic potential for the treatment of various diseases. Selective fluorescence imaging for HDAC6 is important for its pathological and biological studies. However, specific detection of HDAC6 by using a fluorescent small molecule probe remains a great challenge. Herein, a series of fluorescent HDAC6-selective inhibitors incorporating a naphthalimide skeleton were designed and synthesized. A structure-activity relationship study identified that compound JW-1 had the greatest inhibitory activity and superior specificity against HDAC6. JW-1 could substantially increase α-tubulin acetylation and was active against a panel of six cancer cell lines. Photophysical characterization and cellular imaging of MDA-MB-231 cells demonstrated that JW-1 is a highly fluorescent, cell penetrable, small-molecule inhibitor of HDAC6 that can be used for the detection of HDAC6 in complex cellular environments.

The α' subunit of ß-conglycinin and various glycinin subunits of soy are not required to modulate hepatic lipid metabolism in rats.

PURPOSE: This study examined the effect of soy proteins with depletion of different subunits of the two major storage proteins, ß-conglycinin and glycinin, on hepatic lipids and proteins involved in lipid metabolism in rats, since the bioactive component of soy responsible for lipid-lowering is unclear. METHODS: Weanling Sprague Dawley rats were fed diets containing either 20% casein protein in the absence (casein) or presence (casein + ISF) of isoflavones or 20% alcohol-washed soy protein isolate (SPI) or 20% soy protein concentrates derived from a conventional (Haro) or 2 soybean lines lacking the α' subunit of ß-conglycinin and the A1-3 (1TF) or A1-5 (1a) subunits of glycinin. After 8 weeks, the rats were necropsied and liver proteins and lipids were extracted and analysed. RESULTS: The results showed that soy protein diets reduced lipid droplet accumulation and content in the liver compared to casein diets. The soy protein diets also decreased the level of hepatic mature SREBP-1 and FAS in males, with significant decreases in diets 1TF and 1a compared to the casein diets. The effect of the soy protein diets on female hepatic mature SREBP-1, FAS, and HMGCR was confounded since casein + ISF decreased these levels compared to casein alone perhaps muting the decrease by soy protein. A reduction in both phosphorylated and total STAT3 in female livers by ISF may account for the gender difference in mechanism in the regulation and protein expression of the lipid modulators. CONCLUSIONS: Overall, soy protein deficient in the α' subunit of ß-conglycinin and A1-5 subunits of glycinin maintain similar hypolipidemic function compared to the conventional soy protein. The exact bioactive component(s) warrant identification.