MdMYB44-like positively regulates salt and drought tolerance via the MdPYL8-MdPP2CA module in apple.

Abscisic acid (ABA) is involved in salt and drought stress responses, but the underlying molecular mechanism remains unclear. Here, we demonstrated that the overexpression of MdMYB44-like, an R2R3-MYB transcription factor, significantly increases the salt and drought tolerance of transgenic apples and Arabidopsis. MdMYB44-like inhibits the transcription of MdPP2CA, which encodes a type 2C protein phosphatase that acts as a negative regulator in the ABA response, thereby enhancing ABA signaling-mediated salt and drought tolerance. Furthermore, we found that MdMYB44-like and MdPYL8, an ABA receptor, form a protein complex that further enhances the transcriptional inhibition of the MdPP2CA promoter by MdMYB44-like. Significantly, we discovered that MdPP2CA can interfere with the physical association between MdMYB44-like and MdPYL8 in the presence of ABA, partially blocking the inhibitory effect of the MdMYB44-like-MdPYL8 complex on the MdPP2CA promoter. Thus, MdMYB44-like, MdPYL8, and MdPP2CA form a regulatory loop that tightly modulates ABA signaling homeostasis under salt and drought stress. Our data reveal that MdMYB44-like precisely modulates ABA-mediated salt and drought tolerance in apples through the MdPYL8-MdPP2CA module.

Stellate ganglion block ameliorated central post-stroke pain with comorbid anxiety and depression through inhibiting HIF-1α/NLRP3 signaling following thalamic hemorrhagic stroke.

BACKGROUND: Central post-stroke pain (CPSP) is an intractable and disabling central neuropathic pain that severely affects patients' lives, well-being, and socialization abilities. However, CPSP has been poorly studied mechanistically and its treatment remains challenging. Here, we used a rat model of CPSP induced by thalamic hemorrhage to investigate its underlying mechanisms and the effect of stellate ganglion block (SGB) on CPSP and emotional comorbidities. METHODS: Thalamic hemorrhage was produced by injecting collagenase IV into the ventral-posterolateral nucleus (VPL) of the right thalamus. The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Behavioral tests were carried out to examine depressive and anxiety-like behaviors including the open field test (OFT), elevated plus maze test (EPMT), novelty-suppressed feeding test (NSFT), and forced swim test (FST). The peri-thalamic lesion tissues were collected for immunofluorescence, western blotting, and enzyme-linked immunosorbent assay (ELISA). Genetic knockdown of thalamic hypoxia-inducible factor-1α (HIF-1α) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) with microinjection of HIF-1α siRNA and NLRP3 siRNA into the VPL of thalamus were performed 3 days before collagenase injection into the same regions. Microinjection of lificiguat (YC-1) and MCC950 into the VPL of thalamus were administrated 30 min before the collagenase injection in order to inhibited HIF-1α and NLRP3 pharmacologically. Repetitive right SGB was performed daily for 5 days and laser speckle contrast imaging (LSCI) was conducted to examine cerebral blood flow. RESULTS: Thalamic hemorrhage caused persistent mechanical allodynia and anxiety- and depression-like behaviors. Accompanying the persistent mechanical allodynia, the expression of HIF-1α and NLRP3, as well as the activities of microglia and astrocytes in the peri-thalamic lesion sites, were significantly increased. Genetic knockdown of thalamic HIF-1α and NLRP3 significantly attenuated mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. Further studies revealed that intra-thalamic injection of YC-1, or MCC950 significantly suppressed the activation of microglia and astrocytes, the release of pro-inflammatory cytokines, the upregulation of malondialdehyde (MDA), and the downregulation of superoxide dismutase (SOD), as well as mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. In addition, repetitive ipsilateral SGB significantly restored the upregulated HIF-1α/NLRP3 signaling and the hyperactivated microglia and astrocytes following thalamic hemorrhage. The enhanced expression of pro-inflammatory cytokines and the oxidative stress in the peri-thalamic lesion sites were also reversed by SGB. Moreover, LSCI showed that repetitive SGB significantly increased cerebral blood flow following thalamic hemorrhage. Most strikingly, SGB not only prevented, but also reversed the development of mechanical allodynia and anxiety- and depression-like behaviors induced by thalamic hemorrhage. However, pharmacological activation of thalamic HIF-1α and NLRP3 with specific agonists significantly eliminated the therapeutic effects of SGB on mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. CONCLUSION: This study demonstrated for the first time that SGB could improve CPSP with comorbid anxiety and depression by increasing cerebral blood flow and inhibiting HIF-1α/NLRP3 inflammatory signaling.

Comparison of predictive value of risk scores for gastrointestinal bleeding in antiplatelet therapy.

Gastrointestinal bleeding (GIB) is the most common serious bleeding complication of antiplatelet therapy. The bleeding risk score (BRS) of GIB may help to determine the risk of bleeding, and provides a reference for the formulation of antiplatelet therapy regimen in clinical practice, but we found that no specific risk scores are available in East Asian patients. This study analyzed patients who were administered antiplatelet therapy from May 2015 to December 2018 in two medical centers. Patient's baseline data were obtained. We assessed four BRSs (New Score, RIETE Score, Cuschieri Score, de Groot Score) and compared them using the area under the receiver operating characteristic curve (AUC). The 4,052 patients enrolled in this study had an average age of 69.6 ± 10.8 years, and 65.9% of them were male. Among the 4,052 patients included, 171 patients experienced GIB within 6 months of follow-up. In the study population, the AUCs for the New, RIETE, Cuschieri, and de Groot scores were 0.673 (95% confidence interval (CI) 0.616-0.729, P < .001), 0.742 (95% CI 0.690-0.794, P < .001), 0.598 (95% CI 0.537-0.659, P = .002), and 0.875 (95% CI 0.839-0.912, P < .001), respectively. After validation, the de Groot Score has better performance. Among the four scores, the de Groot Score might be more suitable for helping Chinese clinicians to predict the risk of GIB in patients taking antiplatelet drugs, and reduce GIB events.

Systemic lupus erythematosus patients have a distinct structural and functional skin microbiota compared with controls.

OBJECTIVE: The skin is the second most affected organ after articular involvement in systemic lupus erythematosus (SLE) patients. Cutaneous involvement occurs in approximately 80% of patients during the course of SLE. Interaction between the host and skin microorganism is a complex process. There are few studies on the diversity of skin microbes in SLE patients. Therefore, this study aims to explore the relationship between skin microorganisms and SLE. METHODS: A total of 20 SLE patients, 20 controls with rosacea and 20 healthy controls were selected as study subjects. Both the skin microbiota of rash region and non-rash region for each SLE patient were collected.16S rRNA gene sequencing was used to detected skin microbiota from 80 specimens. α-Diversity and ß-diversity of skin microbiota were analyzed based on operational taxonomic units (OTUs) and minimal entropy decomposition (MED). Using Wilcoxon test and Linear Discriminate Analysis Effect Size (LEfSe), skin microbial diversity and composition were analyzed. Functional capabilities of microbiota were estimated through Kyoto Encyclopedia of Genes and Genomes database. RESULTS: Compared to rash region of SLE, diversity and richness were increased in healthy controls, and decreased in non-rash region of SLE and rash region of controls with rosacea. Additionally, changes of skin microbial composition were found at different taxonomic levels between four groups. For example, genus Halomonas was increased and genera Pelagibacterium, Novosphingobium, and Curvibacter were decreased in rash region compared to non-rash region of SLE based on OTUs and MED. Based on OTUs, metabolic pathways were also found differences in SLE patients, such as Xenobiotics Biodegradation and Metabolism. CONCLUSION: Compositions and diversity of skin microbiota in SLE patients are changed. This pilot study provides some suggestive evidence for further exploration of skin microbiota in SLE patients with cutaneous involvement.

Comparison of clinical performance of four gastrointestinal bleeding risk scores in Chinese patients with atrial fibrillation receiving oral anticoagulants.

Gastrointestinal bleeding is the most common bleeding complication during anticoagulant therapy. A reliable bleeding risk score can help the clinician assess risk of bleeding in individual patients and select the anticoagulant regimen. This study retrospectively analyzed the data of patients with atrial fibrillation who received anticoagulant therapy from July 2015 to December 2018 at two centers-the Fujian Medical University Union Hospital and Fuzhou Second Hospital Affiliated to Xiamen University. Demographic data, clinical findings, and laboratory results were collected from the hospital records. Patients were followed up for 6 months. The performance of four bleeding risk scores (New Score, RIETE Score, Cuschieri et al. Score, de Groot et al. Score) for prediction of gastrointestinal bleeding was assessed using the area under the curve. A total of 3462 patients (mean age, 66.3 ± 11.5 years; 59.6% males; 1055 direct oral anticoagulants users and 2407 warfarin users) were followed up for 6 months. While 99/3462 (2.9%) patients had gastrointestinal bleeding. The area under the curves for the New, RIETE, Cuschieri et al., de Groot et al. scores were 0.652 (95% CI 0.576-0.728), 0.862 (95% CI 0.809-0.914), 0.606 (95% CI 0.527-0.685), and 0.873 (95% CI 0.816-0.929), respectively. Among the four BRSs evaluated, the RIETE score and the de Groot et al. score appear to have the good predictive value, while the NEW score and the Cuschieri et al. score did not sufficiently predict gastrointestinal bleeding risk within the study Chinese population.

Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer.

Previous studies show that dopamine D2-like receptor (D2DR) antagonist sulpiride (SUL) enhances the antitumor efficacy of dexamethasone (DEX) in drug-resistant breast cancer involving cancer stem-like cells (CSCs). In this study, we investigated the pharmacokinetic (PK) properties of SUL in nude mice and developed a semi-mechanism PK/PD model to quantitatively characterize the synergistic effect of DEX and SUL in preclinical breast cancer xenografts. After nude mice received oral administration of a single dose of SUL (50 mg/kg, ig), plasma concentrations were assessed using LC-MS/MS. A two-compartment model with double first-order absorption rate was developed to describe the PK profiles of SUL. The pharmacodynamic (PD) study was conducted in nude mice bearing human breast cancer MCF-7/Adr xenografts, which received oral administration of DEX (1, 8 mg·kg-1·d-1) or SUL (25, 50 mg·kg-1·d-1) alone or in various combination. Tumor volumes were measured every other day. The PK model of SUL as well as that of DEX with a time-dependent clearance were integrated into the final PK/PD model both using Hill's function, where DEX exerted its antitumor efficacy by inhibiting the proliferation of tumor cells, and SUL enhanced DEX responses by decreasing the sensitivity parameter EC50. The PK/PD model was evaluated and subjected external validation. Finally, simulations were performed to predict the antitumor efficacy of DEX combined with SUL under various dose regimens, where changing dosing frequency of SUL had little effect, while the antitumor efficacy was predicted to be improved when DEX was given more frequently. The established PK/PD model in this study quantitatively characterizes the antitumor efficacy of the DEX combined with SUL as well as their synergism, and the simulations could provide reference for dose optimization of the combination in future studies.

Comparison of the efficacy of a distal clavicular locking plate with and without a suture anchor in the treatment of Neer IIb distal clavicle fractures.

BACKGROUND: To compare the clinical outcomes between the use of a distal clavicular locking plate alone and the combined use of a plate and a coracoclavicular suture anchor in the treatment of Neer IIb distal clavicle fractures and to discuss the application procedure of suture anchors. METHODS: This is a retrospective study. Thirty-four patients with unilateral Neer IIb distal clavicle fractures who underwent open reduction and internal fixation with a distal clavicular locking plate only (16 patients) or with both a plate and a coracoclavicular suture anchor (18 patients) were evaluated. The main observation data included the Constant-Murley Shoulder Function Score (CMS), rate of postoperative complications, and union time. RESULTS: The distal clavicular locking plate and coracoclavicular suture anchor combination group had better outcomes in the Constant-Murley score (94.6 ± 4.5 vs. 90.1 ± 9.5) (P < 0.05) and a shorter union time (13.9 ± 2.3 vs. 16.1 ± 3.0) (P < 0.05) than the locking plate only group did, and the rate of complications showed no significant difference, 16.7% vs. 31.2% (5/16) (P>0.05). CONCLUSIONS: Both methods achieved good results in the treatment of Neer IIb distal clavicle fractures; however, the use of both locking plates and coracoclavicular suture anchors can provide more stability in the early stage after operation than can the use of locking plates alone, which can make the sped of union quicker and result in better clinical outcomes. For elderly patients with comminuted Neer IIb distal clavicle fractures, a locking plate combined with a suture anchor is recommended to provide more stability in the early stage after the operation.

Clinical evidence of prevention strategies for capecitabine-induced hand-foot syndrome.

Hand-foot syndrome (HFS) is the most common adverse effect of capecitabine-containing chemotherapy. The purpose of this study was to assess the efficacies of various prevention and treatment strategies for capecitabine-induced HFS. Searches of the PubMed and Embase databases were performed to identify relevant studies. The risk ratio (RR) with the corresponding 95% confidence interval (CI) was used as an effect measure to evaluate the efficacies of these prevention and treatment strategies. Publication bias was evaluated using Begg's and Egger's tests. Overall and subgroup analyses were conducted. All statistical analyses were conducted with Stata software version 12.0. Seventeen eligible studies were included. Our results indicated that celecoxib was significantly associated with a lower incidence of grade ≥2 capecitabine-induced HFS without heterogeneity (RR = 0.43, 95% CI = 0.23-0.81, I2  = 0.0%). However, pyridoxine and topical urea/lactic acid were not effective toward preventing capecitabine-induced grade 1, 2, 3, ≥1 or ≥2 HFS. Moreover, pyridoxine was not effective in treating capecitabine-induced HFS. Similar results were obtained by subgroup analysis. Our results indicate that celecoxib has potential prophylactic efficacy for capecitabine-induced HFS. However, pyridoxine and topical urea/lactic acid are not associated with a decrease in the incidence of capecitabine-induced HFS.

BET-inhibition by JQ1 alleviates streptozotocin-induced diabetic cardiomyopathy.

Diabetic cardiomyopathy is a cascade of complex events leading to eventual heart failure in diabetes. JQ1, one of Bromodomain and extra-terminal domain (BET) protein inhibitors, has exerted therapeutic effects on cancer proliferation, inflammation and cardiovascular disease. Recently, JQ1 was reported to protect mice from bleomycin-induced lung fibrosis and reverse the fibrotic response in carbon tetrachloride-induced liver fibrosis. However, its role in diabetic cardiomyopathy remains to be clarified. Our results indicated that JQ1 treatment suppressed cardiac fibrosis and improved cardiac function in a STZ-induced diabetic mouse model. We further used both cardiofibroblasts and cardiomyocytes in vitro to investigate the protective mechanism of JQ1. JQ1 significantly suppressed hyperglycemia-induced cardiofibroblasts proliferation and migration, myofibroblast differentiation, and collagen production. Moreover, JQ1 reduced hyperglycemia-induced apoptosis of cardiomyocytes in vitro and in vivo. Mechanistically, JQ1 treatment could reverse the expression of Caveolin-1, which modulates transforming growth factor-ß1 (TGF-ß1) signaling in cardiofibroblasts and inhibits cardiomyocytes apoptosis. Our findings identify BET inhibitor JQ1 as promising agent for diabetic cardiomyopathy.

Effects of Duloxetine on the Toll-Like Receptor 4 Signaling Pathway in Spinal Dorsal Horn in a Rat Model of Diabetic Neuropathic Pain.

Objective: Although duloxetine has been approved for clinical therapy for diabetic peripheral neuropathic pain, the exact mechanism underlying the anti-allodynic effects in rat models of diabetes mellitus remains obscure. We attempted to identify whether duloxetine exerts anti-allodynic effects via inhibition of the TLR4-Myd88-dependent pathway in diabetic neuropathic pain (DNP) rats. Methods: An animal model of type 1 diabetic neuropathic pain was induced by intraperitoneal streptozotocin in 108 rats randomized into four groups: control, DNP, solvent control + DNP, and DNP + duloxetine. The DNP model establishment was validated, providing the MWT and TWL measurements were less than 80% of the baseline value on d14 after streptozotocin administration. The expressions of TLR4, Myd88, and NF-κB in the spinal dorsal horn were determined 21 days after streptozotocin injection by immunohistochemical assay and Western blot. Results: The results revealed that MWT and TWL in DNP, SC + DNP, and DLX + DNP groups were significantly decreased 14 days after STZ administration vs control (P < 0.05), while the pain thresholds in the DLX + DNP group were partially reversed. The expressions of TLR4, Myd88, and NF-κB in groups C, DNP, and SC + DNP were significantly increased, whereas duloxetine administration significantly downregulated the expressions of TLR4, Myd88, and NF-κB (P < 0.05). Conclusions: Our findings indicated that duloxetine mitigated mechanical and thermal withdrawal thresholds in STZ-injected rats and rescued the overexpression of the TLR4-Myd88-dependent pathway in the spinal dorsal horn in these rats. Whether these changes directly contributed to the reduction of thermal and mechanical withdrawal behavior needs to be further explored.

Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer.

Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg-1·d-1) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg·kg-1·d-1) and DEX (8 mg·kg-1·d-1) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs.

Mechanisms of Lung Cancer Caused By Cooking Fumes Exposure: A Minor Review△.

Cooking fumes (CFs) are mixtures of many toxic components, such as aldehydes, heterocyclic amines, polycyclic aromatic hydrocarbons, fat aerosols and particulate matters. CFs exposure has been proven to be associated with many diseases. Lung cancer takes the leading place among the diseases being reported caused by CFs exposure. Molecular and biochemical studies have found that CFs exposure may lead to lung cancer by gene damage, formation of reactive oxygen species, blockage of related proteins' function, and even cell death. However, reviews about the mechanisms of how CFs exposure leads to lung cancer are still lacking. Elucidation of the mechanisms of lung cancer caused by CFs exposure may provide a new insight into the prevention of lung cancer caused by CFs exposure, as well as laying the foundation for the toxicity study of CFs. In this minor review, the mechanisms of how CFs exposure leads to lung cancer were summarized and discussed.

[Population pharmacokinetics and its application in new drug research].

Population pharmacokinetics is an emerging discipline developed from the combination of classical pharmacokinetic compartment model and statistics principles, which has been received more and more attention in recent years. Population pharmacokinetics plays important roles in all stages of new drug research. In the early preclinical phase, population pharmacokinetic analysis can help to achieve the preliminary prediction of parameters from animal to human, optimize clinical trial designs, and shorten the time required for new drugs from laboratory to clinical trials. In clinical trials and applications stage, population pharmacokinetic research can help researchers investigate the related covariates that affecting pharmacokinetic behavior of patients comprehensively, and find potential drug-drug interactions in clinical. In addition, population pharmacokinetics has a unique advantage in pediatric drug development due to its strong analysis ability of sparse data. This paper provides a summary on the history and methods of population pharmacokinetics, and the application in new drug discovery and development.

[Efficacy and safety of Wanfeile in the treatment of erectile dysfunction: Report of 100　cases and review of the literature].

OBJECTIVE: To investigate the clinical effect and safety of Wanfeile in the treatment of erectile dysfunction (ED). METHODS: Totally 100 ED patients received oral Wanfeile at 100 mg, once every 3 days, for a course of 3 months. We compared the IIEF-5 scores of the patients before and after medication and among the patients with different degrees of ED. We evaluated the total clinical effectiveness of Wanfeile and analyzed adverse reactions. RESULTS: The total effectiveness rate of Wanfeile was 95.6%. All the patients showed significant improvement in the IIEF-5 scores after treatment as compared with the baseline (P <0.05). Adverse reactions were observed in 5 cases (5.50%), all mild and transient. CONCLUSIONS: Wanfeile is safe and efficacious for the treatment of ED.

[The influence of interfered circadian rhythm on pregnancy and neonatal rats].

The aim of this study was to observe the influence of interfered circadian rhythm on pregnancy of rats and growth of neonatal rats, and to explore the relationship between the interfered circadian rhythm and the changes of melatonin and progesterone. Continuous light was used to inhibit melatonin secretion and therefore the interfered circadian rhythm animal model was obtained. The influence of interfered circadian rhythm on delivery of pregnant rats was observed. Serum was collected from rats during different stages of pregnancy to measure the concentrations of melatonin and progesterone. In order to observe the embryo resorption rate, half of pregnant rats were randomly selected to undergo a laparotomy, and the remainder was used to observe delivery and assess the growth of neonatal rats after delivery. The results showed that the interfered circadian rhythm induced adverse effects on pregnancy outcomes, including an increase of embryo resorption rate and a decrease in the number of live births; inhibited the secretion of melatonin along with decreased serum progesterone level; prolonged the stage of labor, but not the duration of pregnancy; and disturbed the fetal intrauterine growth and the growth of neonatal rats. The results suggest that interfered circadian rhythm condition made by continuous light could make adverse effects on both pregnant rats and neonatal rats. The results of our study may provide a way to modulate pregnant women's circadian rhythm and a possibility of application of melatonin on pregnant women.

[Relevant studies on effect of Fuzheng Sanjie recipe in regulating immune microenvironment remodeling of TAMs in Lewis lung cancer mice].

OBJECTIVE: To study the effect of Fuzheng Sanjie recipe in regulating tumor-associated macrophages (TAMs) in Lewis lung cancer mice. METHOD: Efforts were made to establish the Lewis lung cancer mouse model, weigh tumors and calculate the anti-tumor rate. The immunohistochemical method was used to examine the infiltration degree of CD68 + in tumor tissues in each group. ELISA was used to examine the content of IFN-γ, TGF-ß, IL-4, IL-13, IL-6, IL-10, IL-12, TNF-α in mice serum. RESULT: Compared with the tumor-bearing model group, all of the other groups showed higher tumor inhibition rates, i. e. 50.28% for the DDP group, 34.37% for the TCM-preventing group and 66.76% for the Chinese and western medicine group, with statistical difference (P < 0.05), but without statistical difference in the infiltration degree of CD68+. The expressions of the IFN-γ, IL-6, IL-12 in tumor-bearing groups were lower than that in the blank control group, but with higher contents of IL-4, IL-13, TGF-ß. Intervened with different drugs, there were significant differences in content among some relevant cytokines (P < 0.05), as well as statistical differences among the TCM prevention group, the Chinese and western medicine group and the tumor-bearing control group (P <0. 05) , but without statistical difference in TNF-α and IL-10 content from the tumor-bearing control group (P < 0.05). CONCLUSION: Fuzheng Sanjie recipe could reverse the immune remodeling effect and control the tumor growth by down-regulating the expressions of IL-4, IL-13, TGF-α in lung cancer immune microenvironment and up-regulating the expression of IFN-γ.

Three-dimensional conformal radiotherapy in combination with transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma.

PURPOSE: This study aimed to investigate the efficacy and safety of transcatheter arterial chemoembolization (TACE) in combination with three-dimensional conformal radiotherapy (3D-CRT) in the treatment for locally advanced unresectable hepatocellular carcinoma (HCC). METHODS: From March 2000 to March 2009 a total of 158 patients with unresectable HCC treated and followed at our hospital were divided into TACE group (N=80) and TACE combined with 3D-CRT group (N=78). The TACE group was treated 3-6 times. In the combination group, 2-3 TACE courses were administered and 3D-CRT was performed 2 weeks after the last TACE. Three months after the end of treatment, imaging and serum AFP were carried out to assess the treatment efficacy. RESULTS: The response rates of TACE and the combination groups were 53.7% (43/80) and 71.8% (58/78) (p<0.05). The 1, 2, and 3-year survival rates of patients in the TACE and combination groups were 58.75, 36.25, 16.25%, and 78.48, 55.12 and 25.64% (p<0.05), respectively. Treatment compliance was good, with at least 2 TACE administrations for each case and at least 52 Gy for radiotherapy. In the TACE and the combination group, there were 2 and 3 cases with grade III/IV toxicity, respectively, without treatment-related death. CONCLUSION: 3D-CRT in combination with TACE significantly improve the therapeutic outcome in patients with locally advanced unresectable HCC, without creating severe toxicity.

Acetylcholine muscarinic M1 receptors in the rodent prefrontal cortex modulate cognitive abilities to establish social hierarchy.

In most social species, the attainment of social dominance is strongly affected by personality traits. Dominant individuals show better cognitive abilities, however, whether an individual's cognition can determine its social status has remained inconclusive. We found that mice show better cognitive abilities tend to possess a higher social rank after cohousing. The dynamic release of acetylcholine (ACh) in the prelimbic cortex (PL) is correlated with mouse dominance behavior. ACh enhanced the excitability of the PL neurons via acetylcholine muscarinic M1 receptors (M1). Inhibition of M1 impaired mice cognitive performance and induced losing in social competition. Mice with M1 deficiency in the PL performed worse on cognitive behavioral tests, and exhibited lower status when re-grouped with others. Elevating ACh level in the PL of subordinate mice induced winning. These results provide direct evidence for the involvement of M1 in social hierarchy and suggest that social rank can be tuned by altering cognition through cholinergic system.

Dissecting the efficacy of the use of acupuncture and Chinese herbal medicine for the treatment of premature ovarian insufficiency (POI): A systematic review and metaanalysis.

Premature ovarian insufficiency is a multi-factor gynecological disease that has become a major global health problem. In recent years, several trials have explored the treatment of premature ovarian insufficiency using Chinese herbal medicine and acupuncture, but the efficacy and safety of this combination remains controversial. This systematic review and meta-analysis aimed to comprehensively evaluate the efficacy and safety of combining Chinese herbal medicine with acupuncture to treat premature ovarian insufficiency. From eight different databases, we retrieved randomized controlled trials wherein Chinese herbal medicine and acupuncture had been compared with western medicine in the treatment of premature ovarian insufficiency. The bias risk assessment stipulated by the Cochrane Collaboration's tool was utilized to evaluate the quality of the chosen randomized controlled trials. This meta-analysis was executed with the help of Review Manager 5.3 and Stata 10.0. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation framework. A total of 10 randomized controlled trials involving 594 premature ovarian insufficiency patients were included in the analysis. Compared with western medicine, co-treatment with acupuncture and Chinese herbal medicine exhibited a significantly higher total effective rate (relative risk: 1.21; 95% confidence interval: 1.12-1.31; P < 0.01, I2 = 0%), but lower levels of luteinizing hormone (standardized mean difference: -0.57; 95% confidence interval: -1.06, -0.08; P < 0.05, I2 = 80%), follicle-stimulating hormone, and Kupperman index score. Moreover, the combined intervention increased estradiol level in the serum. Overall, the data demonstrate that acupuncture plus Chinese herbal medicine is an efficacious and safe treatment option for POI patients. These findings must be verified by conducting large-scale, multicenter, high-quality, and long-term randomized controlled trials.

D-D and PLR, NLR combined forecasting first-line treatment: The short-term curative effect and prognosis of patients with SCLC.

The aim of this study was to evaluate the difference in D-dimer (D-D) combined with the platelet lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) before treatment in small cell lung cancer (SCLC) patients receiving first-line treatment and to analyze the efficacy and prognosis. We retrospectively collected the records of SCLC patients treated in our hospital from February 2019 to January 2023 and finally included 100 patients. A binary logistic regression analysis method was applied to analyze the relationship between D-D, PLR, and NLR and short-term efficacy. Univariate and multivariate Cox regression analyses were utilized to estimate the individual effect of plasma parameters on progression-free survival (PFS). The optimal cutoff values of D-D, PLR, and NLR for predicting survival outcome were determined by receiver operating characteristic curve analysis. Kaplan-Meier survival analysis was utilized to examine the correlation between D-D, PLR, and NLR the prognosis of SCLC patients. PLR was associated with a short-term curative effect in patients with SCLC (odds ratio: 0.326, 95% confidence interval [CI]: 0.135 0.790). Univariate Cox regression showed that D-D (hazard ratio [HR]: 0.495, 95% CI: 0.323-0.758), PLR (HR:0.420, 95% CI: 0.269-0.655) and NLR (HR: 0.407, 95% CI: 0.263-0.630) were associated with PFS in SCLC patients (P < .05). Multivariate Cox regression analysis showed that PLR (HR: 2.395, 95% CI: 1.468-3.906) and NLR (HR: 2.148, 95% CI: 1.319-3.499) correlated significantly with PFS (P < .05). The optimal cutoff values of D-D, PLR and NLR for predicting PFS were 0.88 mg/L (65.4% and 68.7%), 195.44 (61.5% and 81.2%) and 3.63 (63.5% and 81.2%), respectively, and the corresponding area under receiver (AUC) operating characteristic curve 0.691 (95% CI: 0.587-0.795), 0.721 (95% CI: 0.620-0.822) and 0.714 (95% CI: 0.614-0.815). When D-D was used in combination with PLR or NLR, the corresponding AUCs were 0.737 (95% CI: 0.640-0.835) and 0.761 (95% CI: 0.667-0.855). Pretreatment PLR is an independent predictor of short-term efficacy in SCLC patients. Pretreatment D-D, PLR and NLR are potential biochemical markers for predicting the prognosis of SCLC patients treated with first-line treatment. When D-D is combined with PLR and NLR, it shows stronger predictive ability.