Validation of the Center for Neurologic Study Bulbar Function Scale-Chinese version in a population with amyotrophic lateral sclerosis.

OBJECTIVE: The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) was specifically designed as a self-reported measure of bulbar function. The purpose of this research was to validate the Chinese translation of the CNS-BFSC as an effective measurement for the Chinese population with ALS. METHODS: A total of 111 ALS patients were included in this study. The CNS-BFSC score, three bulbar function items from the ALSFRS-R, and visual analog scale (VAS) score for speech, swallowing and salivation were assessed in the present study. Forty-six ALS patients were retested on the same scale 5-10 days after the first evaluation. RESULTS: The CNS-BFSC sialorrhea, speech and swallowing subscores were separately correlated with the VAS subscores (p < 0.001). The CNS-BFSC total score and sialorrhea and speech scores were significantly correlated with the ALSFRS-R bulbar subscore (p < 0.001). The CNS-BFSC total score and ALSFRS-R bulbar subscale score were highly predictive of a clinician diagnosis of impaired bulbar function (area under the receiver operating characteristic curve, 0.947 and 0.911, respectively; p < 0.001). A cutoff value for the CNS-BFSC total score was selected by maximizing Youden's index; this cutoff score was 33, with 86.4% sensitivity and 93.3% specificity. The CNS-BFSC total score and the sialorrhea, speech and swallowing subscores had good-retest reliability (p > 0.05). The Cronbach's α of the CNS-BFSC was 0.972. CONCLUSION: The Chinese version of the CNS-BFSC has acceptable efficacy and reliability for the assessment of bulbar dysfunction in ALS patients.

Molecular and morphological evidence supports the resurrection of Chrysospleniumguangxiense H.G.Ye & Gui C.Zhang (Saxifragaceae).

Chrysospleniumguangxiense H.G.Ye & Gui C.Zhang was first described as a new species in 1994 but later synonymized in the Flora of China treatment with C.glossophyllum H.Hara. Plastid genomes and nrDNA sequences were used to infer the phylogenetic relationships of selected taxa in Chrysosplenium. Our phylogenetic analyses revealed that C.guangxiense belongs to sect. Alternifolia, is closely related to Chrysospleniumhydrocotylifolium H.Lév. & Vaniot but distant from C.glossophyllum. Morphologically, C.guangxiense could be easily distinguished from C.glossophyllum by having robust rhizomes, basal leaves with a long cuneate base and fewer teeth in the margin, curled sepal margins, and red, larger seeds. It could also be easily distinguished from C.hydrocotylifolium by possessing long elliptic leaves and a long cuneate leaf base. Along with the phylogenetic studies, the complete plastid genome of C.guangxiense was also reported. The plastid genome was 154,004 bp in length and comprised two inverted repeats (IRs) of 28,120 bp, separated by a large single-copy of 80,646 bp and a small single-copy of 17,118 bp. A total of 111 functional genes were discovered, comprising 78 protein-coding genes, 29 tRNA genes, and four rRNA genes. Based on assessment of morphological and molecular data Chrysospleniumguangxiense H.G.Ye & Gui C.Zhang is resurrected from C.glossophyllum H.Hara at species level. A global conservation assessment classifies C.guangxiense as Vulnerable (VU).

Nab-paclitaxel plus S-1 versus nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer: a multicenter, randomized, phase II study.

BACKGROUND: Encouraging antitumor activity of nab-paclitaxel plus S-1 (AS) has been shown in several small-scale studies. This study compared the efficacy and safety of AS versus standard-of-care nab-paclitaxel plus gemcitabine (AG) as a first-line treatment for advanced pancreatic cancer (PC). METHODS: In this multicenter, randomized, phase II trial, eligible patients with unresectable, locally advanced, or metastatic PC were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 125 mg/m2 on days 1 and 8; S-1 twice daily on days 1 through 14) or AG (nab-paclitaxel 125 mg/m2 on days 1 and 8; gemcitabine 1000 mg/m2 on days 1 and 8) for 6 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Between July 16, 2019, and September 9, 2022, 62 patients (AS, n = 32; AG, n = 30) were treated and evaluated. With a median follow-up of 8.36 months at preplanned interim analysis (data cutoff, March 24, 2023), the median PFS (8.48 vs 4.47 months; hazard ratio [HR], 0.402; P = .002) and overall survival (OS; 13.73 vs 9.59 months; HR, 0.226; P < .001) in the AS group were significantly longer compared to the AG group. More patients had objective response in the AS group than AG group (37.50% vs 6.67%; P = .005). The most common grade 3-4 adverse events were neutropenia and leucopenia in both groups, and gamma glutamyl transferase increase was observed only in the AG group. CONCLUSION: The first-line AS regimen significantly extended both PFS and OS of Chinese patients with advanced PC when compared with the AG regimen, with a comparable safety profile. (ClinicalTrials.gov Identifier: NCT03636308).

Clinical efficacy of laparoscopic cholecystectomy combined with endoscopic papillary balloon dilation in treatment of gallbladder stones with common bile duct stones: A retrospective study.

BACKGROUND: The incidence of cholelithiasis has been on the rise in recent years, but the choice of procedure is controversial. AIM: To investigate the efficacy of laparoscopic cholecystectomy (LC) combined with endoscopic papillary balloon dilation (EPBD) in patients with gallbladder stones (GS) with common bile duct stones (CBDS). METHODS: The clinical data of 102 patients with GS combined with CBDS were selected for retrospective analysis and divided into either an LC + EPBD group (n = 50) or an LC + endoscopic sphincterotomy (EST) group (n = 52) according to surgical methods. Surgery-related indexes, postoperative recovery, postoperative complications, and expression levels of inflammatory response indexes were compared between the two groups. RESULTS: Total surgical time, stone free rate, rate of conversion to laparotomy, and successful stone extraction rate did not differ significantly between the LC + EPBD group and LC + EST group. Intraoperative hemorrhage, time to ambulation, and length of hospitalization in the LC + EPBD group were lower than those of the LC + EST group (P < 0.05). The rate of total complications of the two groups was 9.80% and 17.65%, respectively, and the difference was not statistically significant. No serious complications occurred in either group. At 48 h postoperatively, the expression levels of interleukin-6, tumor necrosis factor-α, high-sensitivity C-reactive protein, and procalcitonin were lower in the LC + EPBD group than in the LC + EST group (P < 0.05). At 3 d postoperatively, the expression levels of aspartate transaminase, alanine transaminase, and total bilirubin were lower in the LC + EPBD group than in the LC + EST group (P < 0.05). CONCLUSION: LC combined with EPBD and LC combined with EST are both effective procedures for the treatment of GS with CBDS, in which LC combined with EPBD is beneficial to shorten the patient's hospitalization time, reduce the magnitude of elevated inflammatory response indexes, and promote postoperative recovery.

Double Balloon Combined with Oxytocin in Labor Induction: Analysis of Multivariate Factors Affecting the Efficacy of Cervical Ripening.

Objective: Labor induction during the late trimester of pregnancy is a common option of terminating pregnancy by inducing uterine contractions through medication or cervical mechanical dilation. However, there are few researches on the factors influencing the effectiveness of cervical ripening balloon combined with oxytocin in inducing labor. To explore factors affecting the efficacy of cervical ripening double balloon combined with oxytocin in labor induction. Methods: Using a convenient sampling method, this study retrospectively collected the clinical data of 230 pregnant women who underwent cervical ripening double balloon combined with oxytocin for labor induction in our hospital from September 2021 to August 2022. The included subjects were divided into a vaginal delivery group (n = 180) and a cesarean section group (n = 50) based on the delivery mode for comparing relevant indicators between the two groups. Results: The presence of acute chorioamnionitis (OR = 1.456, 95% CI: 1.257-2.112), fetal distress (OR = 1.371, 95% CI: 1.331-2.633), and the placement of cervical ripening balloon catheter for >12h (OR = 1.563, 95% CI: 1.231-3.263) were risk factors for successful application of cervical ripening double balloon combined with oxytocin for labor induction in pregnant women; while multi-gravidity (OR = 0.736, 95% CI: 0.455-0.875) was a protective factor. In addition, evaluation of the predictive value revealed that acute chorioamnionitis, fetal distress, the placement of cervical ripening balloon catheter for >12h, and gravidity all had certain predictive value for the failure of cervical ripening double balloon combined with oxytocin for labor induction, with the highest predictive value found through joint predictive (AUC: 0.931, 95% CI: 0.714-0.811). Conclusion: Cervical ripening double balloon combined with oxytocin for labor induction may have a high success rate in multigravida. Acute chorioamnionitis, fetal distress, and prolonged placement of the balloon may have a negative impact on the success rate of cervical ripening double balloon combined with oxytocin for labor induction.

Clinical efficacy of Baijin pills in the treatment of generalized tonic-clonic seizure epilepsy with cognitive impairment.

BACKGROUND: The generalized tonic-clonic seizure (GTCS) is the most usual variety of epileptic seizure. It is mainly characterized by strong body muscle rigidity, loss of consciousness, a disorder of plant neurofunction, and significant damage to cognitive function. The effect of antiepileptic drugs on cognition should also be considered. At present, there is no effective treatment for patients with epilepsy, but traditional Chinese medicine has shown a significant effect on chronic disease with fewer harmful side effects and should, therefore, be considered for the therapy means of epilepsy with cognitive dysfunction. AIM: To investigate the clinical efficacy of Baijin pills for treating GTCS patients with cognitive impairment. METHODS: This prospective study enrolled patients diagnosed with GTCS between January 2020 and December 2023 and separate them into two groups (experimental and control) using random number table method. The control group was treated with sodium valproate, and the experimental group was Baijin pills and sodium valproate for three months. The frequency and duration of each seizure, the Montreal Cognitive Assessment Scale (MoCA), and the Quality of Life Rating Scale (QOLIE-31) were recorded before and after treatment. RESULTS: There were 85 patients included (42 in the control group and 43 in the experimental group). After treatment, the seizure frequency in the experimental group was significantly reduced (P < 0.05), and seizure duration was shortened (P < 0.01). The total MoCA score in the experimental group significantly increased compared to before treatment (P < 0.01), and the sub-item scores, except naming and abstract generalization ability, significantly increased (P < 0.05), whereas the total MoCA score in the control group significantly decreased after treatment (P < 0.05). The QOLIE-31 score of the experimental group increased significantly after treatment compared to before treatment (P < 0.01). CONCLUSION: Baijin pills have a good clinical effect on epilepsy with cognitive dysfunction.

Research Progress of Hydrogel Microneedles in Wound Management.

Microneedles are a novel drug delivery system that offers advantages such as safety, painlessness, minimally invasive administration, simplicity of use, and controllable drug delivery. As a type of polymer microneedle with a three-dimensional network structure, hydrogel microneedles (HMNs) possess excellent biocompatibility and biodegradability and encapsulate various therapeutic drugs while maintaining drug activity, thus attracting significant attention. Recently, they have been widely employed to promote wound healing and have demonstrated favorable therapeutic effects. Although there are reviews about HMNs, few of them focus on wound management. Herein, we present a comprehensive overview of the design and preparation methods of HMNs, with a particular emphasis on their application status in wound healing, including acute wound healing, infected wound healing, diabetic wound healing, and scarless wound healing. Finally, we examine the advantages and limitations of HMNs in wound management and provide suggestions for future research directions.

RuCo/ZrO2 Tandem Catalysts with Photothermal Confinement Effect for Enhanced CO2 Methanation.

Photothermal CO2 methanation reaction represents a promising strategy for addressing CO2-related environmental issues. The presence of efficient tandem catalytic sites with a localized high-temperature is an effective pathway to enhance the performance of CO2 methanation. Here the bimetallic RuCo nanoparticles anchored on ZrO2 fiber cotton (RuCo/ZrO2) as a photothermal catalyst for CO2 methanation are prepared. A significant photothermal CO2 methanation performance with optimal CH4 selectivity (99%) and rate (169.93 mmol gcat -1 h-1) is achieved. The photothermal energy of the RuCo bimetallic nanoparticles, confined by the infrared insulation and low thermal conductivity of the ZrO2 fiber cotton (ZrO2 FC), provides a localized high-temperature. In situ spectroscopic experiments on RuCo/ZrO2, Ru/ZrO2, and Co/ZrO2 indicate that the construction of tandem catalytic sites, where the Co site favors CO2 conversion to CO while incorporating Ru enhances CO* adsorption for subsequent hydrogenation, results in a higher selectivity toward CH4. This work opens a new insight into designing tandem catalysts with a photothermal confinement effect in CO2 methanation reaction.

Discovery of 4-(isopentyloxy)-3-nitrobenzamide derivatives as xanthine oxidase inhibitors through a non-anthraquinone exploration.

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 µM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.

Constructing a Cr-Substituted Co-Free Li-Rich Ternary Cathode with a Spinel-Layered Biphase Interface.

Lithium-rich manganese-based layered oxides (LRMOs) have recently attracted enormous attention on account of their remarkably big capacity and high working voltage. However, some inevitable inherent drawbacks impede their wide-scale commercial application. Herein, a kind of Cr-containing Co-free LRMO with a topical spinel phase (Li1.2Mn0.54Ni0.13Cr0.13O2) has been put forward. It has been found that the high valence of Cr6+ can reduce the Li+ ion content and induce the formation of a local spinel phase by combining more Li+ ions, which is beneficial to eliminate the phase boundary between the spinel phase and the bulk phase of the LRMO material, thus dramatically avoiding phase separation during the cycling process. In addition, the introduction of Cr can also expand the layer spacing and construct a stronger Cr-O bond compared with Mn-O, which enables to combine the transition metal (TM) slab to prevent the migration of TM ions and the transformation of the bulk phase to the spinel phase. Simultaneously, the synergistic effect of the successfully constructed spinel-layered biphase interface and the strong Cr-O bond can effectively impede the escape of lattice oxygen during the initial activation process of Li2MnO3 and provide the fast diffusion path for Li+ ion transmission, thus further reinforcing the configurable stability. Besides, Cr-LRMO presents an ultrahigh first discharge specific capacity of 310 mAh g-1, an initial Coulombic efficiency of as high as 92.09%, a good cycling stability (a capacity retention of 94.70% after 100 cycles at 1C), and a small voltage decay (3.655 mV per cycle), as well as a good rate capacity (up to 165.88 mAh g-1 at 5C).

Association Among Vitamin D Supplementation, Serum 25(OH)D Concentrations, and Mortality Risk: A Prospective Cohort Study Using NHANES 2007-2018 Data.

BACKGROUND: To determine the associations among self-reported vitamin D (VD) supplementation, measured serum 25-hydroxyvitamin D (25[OH]D) concentrations, and all-cause and cause-specific mortality risks. METHODS: Self-reported VD supplementation, serum 25(OH)D concentration, and all-cause and cause-specific mortality data from the National Health and Nutrition Examination Survey 2007-2018 were examined for 10,793 adults ≥20 years from the United States. VD dosage was categorized as <800 or ≥800 IU/d. The mortality status and causes of mortality up to 2019 were determined using the National Death Index. The relationships among VD, 25(OH)D levels, and mortality were analyzed using Cox regression before and after propensity score matching (PSM). RESULTS: Over a median of 6.6 years, 915 deaths were recorded, 230 because of cardiovascular disease (CVD), 240 because of cancer, and 445 because of other specific causes. Mortality risk did not differ between VD <800 IU/d and ≥800 IU/d before or after PSM. However, serum 25(OH)D concentrations were statistically different before and after PSM. The upper 2 quartiles of 25(OH)D levels were associated with lower all-cause mortality, and the fourth quartile was associated with reduced other-specific mortality before and after PSM. No correlation was found between the 25(OH)D concentration and CVD- or cancer-specific mortality after PSM. The inverse 25(OH)D-mortality relationship was consistent across subgroups. CONCLUSIONS: Based on this large cohort study, higher 25(OH)D levels are robustly associated with reduced all-cause and other specific mortality but not CVD- or cancer-specific mortality. These findings support the benefits of maintaining adequate VD status for longevity. Further research is required to elucidate these mechanisms and define the optimal VD concentration to reduce mortality. These results underscore the importance of public health strategies for preventing VD deficiency.

Regulation of tillage on grain matter accumulation in maize.

Introduction: To address issues related to shallow soil tillage, low soil nutrient content, and single tillage method in maize production in the Western Inner Mongolia Region, this study implemented various tillage and straw return techniques, including strip cultivation, subsoiling, deep tillage, no-tillage, straw incorporation with strip cultivation, straw incorporation with subsoiling, straw incorporation with deep tillage, and straw incorporation with no tillage, while using conventional shallow spinning by farmers as the control. Methods: We employed Xianyu 696 (XY696) and Ximeng 6 (XM6) as experimental materials to assess maize 100-grains weight, grain filling rate parameters, and grain nutrient quality. This investigation aimed to elucidate how tillage and straw return influence the accumulation of grain material in different maize varieties. Results and discussion: The results indicated that proper implementation of tillage and straw return had a significant impact on the 100-grains weight of both varieties. In comparison to CK (farmer's rotary rotation), the most notable rise in 100-grains weight was observed under the DPR treatment (straw incorporation with deep tillage), with a maximum increase of 4.84% for XY696 and 6.28% for XM6. The proper implementation of tillage and straw return in the field resulted in discernible differences in the stages of improving the grain filling rates of different maize varieties. Specifically, XY696 showed a predominant increase in the filling rate during the early stage (V1), while XM6 exhibited an increase in the filling rates during the middle and late stages (V2 and V3). In comparison to CK, V1 increased by 1.54% to 27.56% in XY696, and V2 and V3 increased by 0.41% to 10.42% in XM6 under various tillage and straw return practices. The proper implementation of tillage and straw return had a significant impact on the nutritional quality of the grains in each variety. In comparison to CK, the DPR treatment resulted in the most pronounced decrease in the soluble sugar content of grains by 25.43% and the greatest increase in the crude fat content of grains by 9.67%. Conclusion: Ultimately, the proper implementation of soil tillage and straw return facilitated an increase in grain crude fat content and significantly boosted grain weight by improving the grouting rate parameters at all stages for various maize varieties. Additionally, the utilization of DPR treatment proved to be more effective. Overall, DPR is the most promising strategy to improve maize yield and the nutritional quality of grain in the long term in the Western Inner Mongolia Region.

Socioeconomic disparity in the natural history of cutaneous melanoma: evidence from two large prospective cohorts.

BACKGROUND: Previous studies on the associations between socioeconomic status (SES) and cutaneous malignant melanoma (CMM) failed to distinguish the effects of different SES factors under an individual-data-based prospective study design. METHODS: Based on UK Biobank (UKB) and China Kadoorie Biobank (CKB), we estimated the effects of four SES factors on transitions from baseline to CMM in situ, subsequently to invasive CMM and further CMM mortality by applying multistate models. We further explored to which extent the associations between SES and CMM incidence could be explained by potential mediators including sun exposure, lifestyle and ageing in UKB. RESULTS: In multistate analyses, good household income was independently associated with an increased risk of CMM in situ (HR=1.38, 95% CI: 1.21 to 1.58) and invasive CMM (HR=1.34, 95% CI: 1.22 to 1.48) in UKB. These findings were partly validated in CKB. Especially in UKB, we observed an increased risk of CMM in situ and invasive CMM among participants with good type of house; only good education was independently associated with lower risk of evolving to invasive CMM among patients with CMM in situ (HR=0.69, 95% CI: 0.52 to 0.92); only good household income was independently associated with lower risk of CMM mortality among patients with CMM (HR=0.65, 95% CI: 0.45 to 0.95). In mediation analysis, the proportions attributable to the mediating effect were <6% for all selected variables, including self-reported sun exposure-related factors. CONCLUSION: SES factors have different effects on the incidence and progression of CMM. The association between SES and incident CMM is neither causal nor well explained by selected mediators.

Impact of task-oriented training based on acupuncture rehabilitation on upper extremity function and quality of life of patients with early stroke.

BACKGROUND: Eighty percent of stroke patients develop upper limb dysfunction, especially hand dysfunction, which has a very slow recovery, resulting in economic burden to families and society. AIM: To investigate the impact of task-oriented training based on acupuncture therapy on upper extremity function in patients with early stroke. METHODS: Patients with early stroke hemiplegia who visited our hospital between January 2021 and October 2022 were divided into a control group and an observation group, each with 50 cases. The control group underwent head acupuncture plus routine upper limb rehabilitation training (acupuncture therapy). In addition to acupuncture and rehabilitation, the observation group underwent upper limb task-oriented training (30 min). Each group underwent treatment 5 d/wk for 4 wk. Upper extremity function was assessed in both groups using the Fugl-Meyer Assessment-Upper Extremity (FMA-UE), Wolf Motor Function Rating Scale (WMFT), modified Barthel Index (MBI), and Canadian Occupational Performance Measure (COPM). Quality of life was evaluated using the Short-Form 36-Item Health Survey (SF-36). Clinical efficacy of the interventions was also evaluated. RESULTS: Before intervention, no significant differences were observed in the FMA-UE, MBI, and WMFT scores between the two groups (P > 0.05). After intervention, the FMA-UE, WMFT, MBI, COPM-Functional Mobility and Satisfaction, and SF-36 scores increased in both groups (P < 0.05), with even higher scores in the observation group (P < 0.05). The observation group also obtained a higher total effective rate than the control group (P < 0.05). CONCLUSION: Task-oriented training based on acupuncture rehabilitation significantly enhanced upper extremity mobility, quality of life, and clinical efficacy in patients with early stroke.

Clinical Features and Histopathological Analysis of Oral Lichen Planus: An Analysis of 105 Chinese Patients.

PURPOSE: To study the clinical and pathological characteristics of oral lichen planus (OLP) in a large sample. MATERIALS AND METHODS: A comprehensive analysis was conducted on 105 patients with oral lichen planus (OLP), considering various factors including sex, age, disease site, lesion type, lesion area, morphological characteristics, self-reported symptoms, and history of systemic diseases. Histopathological examination was performed for each patient, and the pathology results were analysed according to sex and age group. RESULTS: 70.5% of the OLP patients were female, and OLP was most likely to occur in the cheek, followed by the tongue, lips, gums and palate. The patients with moderate pain according to the VAS score accounted for 60%. Thirty-nine percent of the OLP patients had a systemic disease, and the most common clinical type of OLP was nonerosive. Most of the pathological results showed liquefaction degeneration of basal cells and infiltration of lamina propria lymphocytes. There was no statistically significant difference in pathological manifestations between male and female patients, and there were statistically significant differences in pathological manifestations among different ages patients. CONCLUSION: This study analysed the sociodemographic data and clinical manifestations of 105 OLP patients to guide follow-up treatment planning and disease monitoring. Moreover, pathological manifestations should be analysed to avoid delayed treatment and to monitor for carcinogenesis. Furthermore, the correlation of pathological manifestations among OLP patients with different sexes and ages is conducive to further research on the specific differential manifestations and possible underlying mechanisms involved.

Discovery of Phenylpyrazole Derivatives as a New Class of Selective Inhibitors of MCL-1 with Antitumor Activity.

MCL-1, an antiapoptotic member of the BCL-2 family, is dysregulated and overexpressed in various tumors. In tumors with MCL-1 overexpression, selective inhibitors of MCL-1 are expected to overcome the drug resistance caused by BCL-2 inhibitors currently used in clinical treatment. Here, we employed docking-based virtual screening to identify an active hit, LC126, with binding affinity around 10 µM for MCL-1 and BCL-2. Under the guidance of structure-based design, we obtained a few selective inhibitors of MCL-1 after three rounds of structural optimization. The representative compound GQN-B37-E exhibited binding affinity for MCL-1 at the submicromolar range (K i = 0.6 µM) without apparent binding to BCL-2 or BCL-XL. 15N-heteronuclear single-quantum coherence NMR spectra suggested that this compound binds to the BH3-domain-binding pocket in the MCL-1 surface. Cellular assays revealed that GQN-B37-Me, the precursor of GQN-B37-E, is effective particularly on leukemia cells (such as H929 and MV-4-11) to induce caspase-dependent apoptosis. Its interaction with MCL-1 in cells was confirmed by coimmunoprecipitation. Administration of GQN-B37-Me to MV-4-11 xenograft mice at 50 mg/kg every 2 days for 20 days led to 43% tumor growth inhibition. GQN-B37-Me also exhibited reasonable in vitro stability in GSH and liver microsomes from several species. This new class of MCL-1 inhibitor may have potential to be further developed into a preclinical candidate for treating leukemia.

Factors linked to prognosis in children with provisional tic disorder: a prospective cohort study.

The purpose of the present study was to estimate the factors linked to the prognosis of children with provisional tic disorder (PTD). We conducted a prospective cohort study enrolled children with PTD who were subsequently followed-up at three-month intervals for 1 year post-enrolment. A total of 259 PTD patients were included in the final analysis. At the end of the follow-up period, 77 (30%) of the patients had achieved clinical remission. Result of the LASSO logistic regression analysis revealed that a disease duration >3 months (OR=4.20, 95% CI 1.20-14.73), moderate/severe tic severity (OR=5.57, 95% CI 2.26-13.76), and comorbid behavioral problems (OR=2.78, 95% CI 1.15-6.69) were significant factors linked to remission in the PTD patients. The path analysis model showed that comorbid behavioral problems and recurrence partially mediated the association between tic severity and remission, with a mediating effect of 37%. Conclusions: We have identified several significant factors linked to prognosis in children with PTD, including comorbid behavioral problems and recurrence, which were found to be important mediators. These findings provide new insights for the clinical management of patients with PTD.

Histone deacetylase complexes: Structure, regulation and function.

Histone deacetylases (HDACs) are key epigenetic regulators, and transcriptional complexes with deacetylase function are among the epigenetic corepressor complexes in the nucleus that target the epigenome. HDAC-bearing corepressor complexes such as the Sin3 complex, NuRD complex, CoREST complex, and SMRT/NCoR complex are common in biological systems. These complexes activate the otherwise inactive HDACs in a solitary state. HDAC complexes play vital roles in the regulation of key biological processes such as transcription, replication, and DNA repair. Moreover, deregulated HDAC complex function is implicated in human diseases including cancer. Therapeutic strategies targeting HDAC complexes are being sought actively. Thus, illustration of the nature and composition of HDAC complexes is vital to understanding the molecular basis of their functions under physiologic and pathologic conditions, and for designing targeted therapies. This review presents key aspects of large multiprotein HDAC-bearing complexes including their structure, function, regulatory mechanisms, implication in disease development, and role in therapeutics.