Whole-genome sequencing reveals genomic diversity and selection signatures in Xia'nan cattle.

BACKGROUND: The crossbreeding of specialized beef cattle breeds with Chinese indigenous cattle is a common method of genetic improvement. Xia'nan cattle, a crossbreed of Charolais and Nanyang cattle, is China's first specialized beef cattle breed with independent intellectual property rights. After more than two decades of selective breeding, Xia'nan cattle exhibit a robust physique, good environmental adaptability, good tolerance to coarse feed, and high meat production rates. This study analyzed the population genetic structure, genetic diversity, and genomic variations of Xia'nan cattle using whole-genome sequencing data from 30 Xia'nan cattle and 178 published cattle genomic data. RESULT: The ancestry estimating composition analysis showed that the ancestry proportions for Xia'nan cattle were mainly Charolais with a small amount of Nanyang cattle. Through the genetic diversity studies (nucleotide diversity and linkage disequilibrium decay), we found that the genomic diversity of Xia'nan cattle is higher than that of specialized beef cattle breeds in Europe but lower than that of Chinese native cattle. Then, we used four methods to detect genome candidate regions influencing the excellent traits of Xia'nan cattle. Among the detected results, 42 genes (θπ and CLR) and 131 genes (FST and XP-EHH) were detected by two different detection strategies. In addition, we found a region in BTA8 with strong selection signals. Finally, we conducted functional annotation on the detected genes and found that these genes may influence body development (NR6A1), meat quality traits (MCCC1), growth traits (WSCD1, TMEM68, MFN1, NCKAP5), and immunity (IL11RA, CNTFR, CCL27, SLAMF1, SLAMF7, NAA35, and GOLM1). CONCLUSION: We elucidated the genomic features and population structure of Xia'nan cattle and detected some selection signals in genomic regions potentially associated with crucial economic traits in Xia'nan cattle. This research provided a basis for further breeding improvements in Xia'nan cattle and served as a reference for genetic enhancements in other crossbreed cattle.

Genomic characterization of dryland adaptation in endangered Anxi cattle in China.

Local species exhibit distinctive indigenous characteristics while showing unique productive and phenotypic traits. However, the advent of commercialization has posed a substantial threat to the survival of indigenous species. Anxi cattle, an endangered native breed in China, have evolved unique growth and reproductive characteristics in extreme desert and semidesert ecosystems. In this study, we conducted a genomic comparison of 10 Anxi cattle genomes with those of five other global populations/breeds to assess genetic diversity and identify candidate genomic regions in Anxi cattle. Population structure and genetic diversity analyses revealed that Anxi cattle are part of the East Asian cattle clade, exhibiting higher genetic diversity than commercial breeds. Through selective sweep analysis, we identified specific genetic variations linked to the environmental adaptability of Anxi cattle. Notably, we identified several candidate genes, including CERS3 involved in regulating skin permeability and antimicrobial functions, RBFOX2 associated with cardiac development, SLC16A7 participated in the regulation of pancreatic endocrine function, and SPATA3 related to reproduction. Our findings revealed the distinctive genomic features of Anxi cattle in dryland environments, provided invaluable insights for further research and breed preservation, and had important significance for enriching the domestic cattle breeding gene bank.

Adrenomedullin, transcriptionally regulated by vitamin D receptors, alleviates atherosclerosis in mice through suppressing AMPK-mediated endothelial ferroptosis.

PURPOSE: Vitamin D receptors (VDR) play important roles in cardiovascular, immune, metabolic and other functions. Activation of VDR may help improve endothelial dysfunction, atherosclerosis, vascular calcification, and cardiac hypertrophy. However, the specific target genes and mechanisms of VDR in improving Human Umbilical Vein Endothelial Cell (HUVEC) functions remain unclear. This study aims to investigate the function and mechanism of VDR in HUVECs. METHODS: Endothelial dysfunction cell model was constructed by oxidized low-density lipoprotein (ox-LDL). An animal model of atherosclerosis was established in male homozygous Apoe-/- mice (6 weeks) on a high fat diet for 6 weeks. The relationship between VDR and adrenomedullin (ADM) was studied by bioinformatics analysis, ChIP, and luciferase reporter gene analysis. Endothelial cell function was evaluated by Transwell migration and Tube Formation tests. Ferroptosis was detected by measuring intracellular iron content, levels of oxidative stress markers, and ferroptosis related proteins. RESULTS: Overexpression of VDR in HUVECs inhibits ox-LDL-induced endothelial dysfunction and ferroptosis. VDR binds to the ADM promoter sequence and regulates the transcription of ADM. Inhibition of ADM promotes ox-LDL-induced endothelial dysfunction and ferroptosis. ADM regulates ox-LDL-induced endothelial dysfunction and ferroptosis through the AMPK signaling pathway. Overexpression of VDR in Apoe-/- mice inhibited lipid deposition and plaque area in atherosclerotic mice. CONCLUSION: VDR inhibits ox-LDL-induced endothelial dysfunction and ferroptosis by regulating ADM transcription and acting on AMPK signaling pathway. Overexpression of VDR in Apoe-/- mice reduced lipid deposition and plaque area in the thoracic aorta of atherosclerotic mice.

A constrained maximum likelihood approach to developing well-calibrated models for predicting binary outcomes.

The added value of candidate predictors for risk modeling is routinely evaluated by comparing the performance of models with or without including candidate predictors. Such comparison is most meaningful when the estimated risk by the two models are both unbiased in the target population. Very often data for candidate predictors are sourced from nonrepresentative convenience samples. Updating the base model using the study data without acknowledging the discrepancy between the underlying distribution of the study data and that in the target population can lead to biased risk estimates and therefore an unfair evaluation of candidate predictors. To address this issue assuming access to a well-calibrated base model, we propose a semiparametric method for model fitting that enforces good calibration. The central idea is to calibrate the fitted model against the base model by enforcing suitable constraints in maximizing the likelihood function. This approach enables unbiased assessment of model improvement offered by candidate predictors without requiring a representative sample from the target population, thus overcoming a significant practical challenge. We study theoretical properties for model parameter estimates, and demonstrate improvement in model calibration via extensive simulation studies. Finally, we apply the proposed method to data extracted from Penn Medicine Biobank to inform the added value of breast density for breast cancer risk assessment in the Caucasian woman population.

A phase 1b study of glasdegib + azacitidine in patients with untreated acute myeloid leukemia and higher-risk myelodysplastic syndromes.

This phase 1b study evaluated glasdegib (100 mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug-drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2-14.0) months and 15.8 (9.3-21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits.Trial registration: ClinicalTrials.gov NCT02367456.

Alternative Pathway to Phase Down Coal Power and Achieve Negative Emission in China.

Although widely recognized as the key to climate goals, coal "phase down" has long been argued for its side effects on energy security and social development. Retrofitting coal power units with biomass and coal co-firing with a carbon capture and storage approach provides an alternative way to avoid these side effects and make deep carbon dioxide emission cuts or even achieve negative emission. However, there is a lack of clear answers to how much the maximum emission reduction potential this approach can unlock, which is the key information to promote this technology on a large scale. Here, we focus on helping China's 4536 coal power units make differentiated retrofit choices based on unit-level heterogeneity information and resource spatial matching results. We found that China's coal power units have the potential to achieve 0.4 Gt of negative CO2 emission in 2025, and the cumulative negative CO2 emission would reach 10.32 Gt by 2060. To achieve negative CO2 emission, the biomass resource amount should be 1.65 times the existing agricultural and forestry residues, and the biomass and coal co-firing ratio should exceed 70%. Coal power units should grasp their time window; otherwise, the maximum negative potential would decrease at a rate of 0.35 Gt per year.

Urotensin II activates the ferroptosis pathway through circ0004372/miR-124/SERTAD4 to promote the activation of vascular adventitial fibroblasts.

Both vascular adventitial fibroblasts (VAFs) and urotensin II (UII) play important roles in vascular remodeling diseases, but the mechanism of UII in VAFs is still unclear. UII inhibited miR-124 expression through up-regulating circ0004372 expression, thereby promoting SERTAD4 expression. UII significantly promoted the generation of ROS, MDA and 4-HNE, reduced the activities of SOD, GST and GR, increased Fe2+ concentration and inhibited GPX4 expression through circ0004372/miR-124/SERTAD4. Both UII and ferroptosis inducer Erastin significantly promoted the expression of α-SMA, Collagen I and TGF-ß1 in VAFs, but circ0004372 siRNA, miR-124 mimics, SERTAD4 siRNA or Ferrostatin-1 significantly inhibited the effect of UII and Erastin on cell activation. When co-transfected with circ0004372 siRNA and miR-124 inhibitors or miR-124 mimics and SERTAD4 overexpression vector, UII still significantly increased the expression of α-SMA, Collagen I and TGF-ß1. After transfection with circ0004372 overexpression vector, miR-124 inhibitors or SERTAD4 overexpression vector and then treating with UII and Ferrostatin-1, the expression of α-SMA, Collagen I and TGF-ß1 was still significant; when the circ0004372 overexpression vector and miR-124 mimics or miR-124 inhibitors and SERTAD4 siRNA were co-transfected and then UII and Ferrostatin-1 were added, the expression of α-SMA, Collagen I and TGF-ß1 was not significantly increased. Therefore, these results indicate that UII promotes the activation of VAFs through the circ0004372/miR-124/SERTAD4/ferroptosis pathway.

Salidroside alleviates diabetic neuropathic pain through regulation of the AMPK-NLRP3 inflammasome axis.

High glucose (HG)-induced nucleotide-binding and oligomerization (NACHT) domain, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome activation leads to diabetic neuropathic pain. We recently showed that salidroside could suppress NLRP3 inflammasome activation in hepatocytes exposed to HG. The aim of this study was to evaluate the analgesic effect of salidroside on diabetic rats and to explore its underlying mechanisms. Rat models with diabetic neuropathic pain were induced by high-fat diet feeding combined with low dose streptozotocin injections. Doses of salidroside at 50 and 100 mg.kg-1.day-1 were administered by gavage to diabetic rats for 6 weeks. Mechanical allodynia test, thermal hyperalgesia test and biochemical analysis were performed to evaluate therapeutic effects. Primary dorsal root ganglion (DRG) cells exposed to HG at 45 mM were used to further study the effects of salidroside on the AMP-activated protein kinase (AMPK)-NLRP3 inflammasome axis and insulin sensitivity in vitro. Salidroside administration improved hyperglycemia, ameliorated insulin resistance, and alleviated neuropathic pain in diabetic rats. Moreover, salidroside induced AMPK activation and suppressed NLRP3 inflammasome activation in the DRGs of diabetic rats. In addition, salidroside treatment relieved oxidative stress, improved insulin sensitivity and regulated the AMPK-NLRP3 inflammasome axis in HG-treated DRGs in vitro. Furthermore, AMPK inhibition in vivo or AMPK silencing in vitro abolished the beneficial effects of salidroside on diabetic neuropathic pain. Together, these results indicate that salidroside alleviates diabetic neuropathic pain through its regulation of the AMPK-NLRP3 inflammasome axis in DRGs.

Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial.

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325-0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395-1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151-0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days' therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.

Differential flora in the microenvironment of lung tumor and paired adjacent normal tissues.

Recent evidence demonstrates the existence of diversified microbiota in the lung. However, the effect of lung carcinogenesis on the flora in lung microenvironment has yet not been well investigated. In this study, we surveyed the microbial composition and diversity in lung tumor and paired adjacent normal tissues obtained from 55 lung cancer patients to test whether any specific tumor-associated microbial features in lung microenvironment can be identified. Compared with non-malignant adjacent tissues, the tumor samples showed significantly lower community richness (α diversity), but no significant difference in overall microbiome dissimilarity (ß diversity). Strong intrasubject correlations were observed between tumor sample and its paired non-malignant adjacent tissues. In addition, correlation network analysis found more significant taxa-taxa correlations (adjusted q-value < 0.05) in tumor microenvironment than non-malignant adjacent tissues. At taxa level, we found Propionibacterium genus were significantly reduced in tumor tissues compared with non-malignant adjacent tissues. In summary, the microbiota in tumor tissues showed the lower richness, higher taxa-taxa interaction, and reduction of potential pro-inflammatory microbial genera compared with non-malignant tissues, suggesting the potential link between the tumor microbiota and the altered tumor microenvironment for the further investigation.

Tanshinone IIA attenuates high glucose induced human VSMC proliferation and migration through miR-21-5p-mediated tropomyosin 1 downregulation.

The proliferation and migration of vascular smooth muscle cells (VSMCs) play important roles in the development and progression of diabetes-related vascular complications. Recently, microRNAs (miRNAs) have been suggested to be involved in the pathogenesis of vascular diseases. This study was designed to investigate the influences of tanshinone IIA, an active compound extracted from Chinese herb Salvia miltiorrhiza, on the proliferation and migration of human aortic VSMCs (HASMCs). cultured in a high glucose medium and the underlying mechanisms related miRNAs. Using a miRNA microarray method, we profiled the miRNA expression signature in human aortic VSMCs (HASMCs) exposed to normal glucose, high glucose with and without Tanshinone IIA. Cell proliferation was measured with 5-bromo-2'-deoxyuridine (BrdU) incorporation assay. Cell migration was evaluated using transwell migration assay and wound scratch assay. Western blot was used to examine the expression of tropomyosin 1 (TPM1) and miRNA level was quantified by real-time PCR. The results showed that several miRNAs that were highly expressed in the high glucose group were significantly decreased in the high glucose with Tanshinone IIA group compared with the normal glucose group (P < 0.05). Among these miRNAs, miR-21-5p was significantly upregulated in the high glucose group and downregulated after Tanshinone IIA treatment (P < 0.05). The depletion of miR-21-5p in HASMCs resulted in decreased cell proliferation and migration (P < 0.05). Moreover, we found that Tanshinone IIA inhibited proliferation and migration partly through miR-21-5p-mediated TPM1 downregulation (P < 0.05). In conclusion, the present study demonstrates that Tanshinone IIA is able to protect HASMCs from high glucose-induced proliferation and migration through regulating expression of miRNAs.

Study on auto bias control of a silicon optical modulator in a four-level pulse amplitude modulation format.

Recently, the high-speed silicon optical modulator has played a greater and greater role in optic fiber communication. Due to the silicon material nonlinear electro-optic effect, the quadrature (Quad) bias point of the modulator is difficult to be locked precisely. In this paper, a novel automatic bias control (ABC) method for four-level pulse amplitude modulation format silicon modulator is presented. First, a sinusoidal dither signal is applied to the modulator DC bias, and the normalized output optical signal function, which is modulated by the dither signal, is obtained. Then, a pair of orthogonal reference functions is created, whose numerical size is equal to the absolute value of sinusoidal and cosine functions so that the frequency is the same as the dither signal. Through the cross-correlation integral operation between the normalized and reference functions above, we find that the zero point of the above integral operation is the best Quad bias point through numerical simulation and experiment. The phase accuracy error of ABC is lower than 2 deg, and it satisfies the business specifications of a high-speed silicon optical modulator.

Circulating MiR-146a May be a Potential Biomarker of Coronary Heart Disease in Patients with Subclinical Hypothyroidism.

BACKGROUND/AIMS: Subclinical hypothyroidism (SCH) plays a crucial role in the development and progression of coronary heart disease (CHD). However, any associated changes in the circulating microRNAs (miRNAs) levels and slightly elevated thyroid stimulating hormone (TSH) levels in CHD patients are unknown. miR-146a is a well known miRNA associated with inflammatory autoimmune diseases. Here, we evaluated miR-146a expression in patients, with the goal of re-evaluating the effect of SCH on CHD. METHODS: A total of 192 study subjects who underwent coronary angiography for either suspected or confirmed CHD were enrolled in 3 groups: CHD with SCH, CHD alone, and healthy controls. The circulating levels of miR-146a were quantified using qRT-PCR. RESULTS: Levels of miR-146a were positively correlated with CHD severity, as indicated by the Gensini score (r=0.354). The relative expression of miR-146a in the CHD+SCH, CHD and healthy control groups was 2.223±0.827, 1.588±0.726 and 0.632±0.309, respectively. Plasma TSH levels were positively correlated with miR-146a levels (r=0.321). According to multivariate logistic regression analyses, miR-146a levels were associated with the incidence of CHD in patients with SCH. For diagnosing CHD, the area under the ROC curve (AUC) of miR-146a and TSH was 0.779 and 0.752, respectively. When the TSH and miR-146a levels were combined to form a composite panel, the AUC of the panel was 0.858. CONCLUSION: Plasma miR-146a levels correlated with the severity of coronary atherosclerosis and increased with TSH slightly elevated in patients with CHD. Thus, miR-146a may have good predictive value for CHD among individuals with elevated TSH levels.

Systemic chemotherapy in combination with liver-directed therapy improves survival in patients with pancreatic adenocarcinoma and synchronous liver metastases.

OBJECTIVES: We investigated whether the combination of systemic chemotherapy (SCT) and liver-directed therapy (LDT) was superior to chemotherapy alone for patients with pancreatic adenocarcinoma and synchronous liver metastases (PACLM). METHODS: We reviewed the medical records of 184 patients treated with SCT ±â€¯LDT at Tianjin Medical University Cancer Hospital from 2001 to 2015. Overall survival (OS) was the primary end-point. The role of treatment modality and other clinical factors was evaluated by univariate and Cox regression analyses. RESULTS: Sixty-four (34.8%) patients in the SCT-LDT group and 120 (65.2%) patients in the SCT group were included in the analysis. Baseline clinical characteristics were similar between the groups (all P > 0.05). The median survival was 8.7 months in the SCT-LDT group and was 6.3 months in the SCT group. The 0.5-, 1-, 2- and 3-year survival rates were 67.2%, 33.4%, 13.3% and 8.9%, respectively, after SCT-LDT, and were 54.9%, 19.0%, 4.5% and 2.0%, respectively, after SCT (P = 0.01). Primary tumor size, ascites, and treatment modality (SCT + LDT vs. SCT) independently predicted survival (P < 0.05). The clinical efficacy congruously favored the SCT-LDT group across the majority of subgroups. CONCLUSIONS: SCT combined with LDT was well tolerated and may be effective to improve survival of patients with PACLM. Ascites and large primary tumor size were poor prognostic factors associated with survival.

Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results.

Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day cycles from day -3, with intravenous cytarabine 100 mg/m2 on days 1-7 and daunorubicin 60 mg/m2 on days 1-3. Patients in remission then received consolidation therapy (2-4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27-75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7-54.1) achieved investigator-reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9-48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4-19.3) months, with 12-month survival probability 66.6% (80% CI 58.5-73.4). The most common treatment-related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high-risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.

Magnesium Citrate Protects Against Vascular Calcification in an Adenine-induced Chronic Renal Failure Rat Model.

BACKGROUND: Hypomagnesemia was identified as a strong risk factor for cardiovascular disease in patients with chronic renal failure (CRF). However, the effects of magnesium (Mg) on vascular calcification (VC) have not been fully elucidated. Thus, we aim to determine the effects of Mg citrate (MgCit) on VC in CRF rats. METHODS: Rats were divided into 5 groups: group 1 (normal diet), group 2 (normal diet with MgCit), group 3 (the VC model of CRF induced by 0.75% adenine and 0.9% phosphorus diet from day 1 to day 28), group 4 (group 3 treated with low-dose MgCit from day 1 to day 42), and group 5 (same as group 3 except the high-dose MgCit). All rats were killed at day 43 with collection of blood and aortas. Then, serum biochemical parameters, VC-related staining, calcium and P contents, alkaline phosphatase contents and activity, expression of alpha smooth muscle actin, and runt-related transcription factor 2 (RUNX2) in aortas were assessed. RESULTS: Group 3 had extensive VC. The VC degree decreased in groups 4 and 5 in a dose-depended manner with reduced calcium content, P levels, alkaline phosphatase content and activity, and protein levels of RUNX2 and increased protein levels of alpha smooth muscle actin in aortas. CONCLUSIONS: MgCit exerted a protective role in VC in adenine-induced CRF rats; thus, it may be a potential drug for the prevention of VC in patients with CRF.

High power, high SMSR and wide tuning range silicon micro-ring tunable laser.

An external cavity tunable laser, which is based on a silicon hybrid micro-ring resonator, is demonstrated. The heat isolate grooves around the rings effectively cuts off temperature crosstalk. Experimental results have shown that the output power of this device can reach 15.5dBm, with a linewidth less than 130 kHz. The tuning range is more than 57nm in C-band with 60 dB side mode suppression ratio (SMSR).

Factors influencing survival of patients with pancreatic adenocarcinoma and synchronous liver metastases receiving palliative care.

BACKGROUND AND AIMS: Patients with pancreatic ductal adenocarcinoma and synchronous liver metastases (PACLM) have an extremely limited life expectancy. We performed a single-center analysis to explore the clinical results and prognostic factors of patients with PACLM receiving palliative care. METHODS: We retrospectively reviewed 189 patients undergoing palliative care at Tianjin Medical University Cancer Hospital over a 15-year period. Clinical characteristics, survival condition, and factors associated with survival were analyzed. Treatment methods included palliative bypass surgery, percutaneous transhepatic cholangiodrainage, drug analgesia, symptomatic treatment, and other nutritional or supportive measures. RESULTS: The overall survival (OS) was 3.6 months for all patients. Multivariate analysis for clinical features showed that Karnofsky performance score (KPS), ascites, cigarette smoking, primary tumor size, and lactate dehydrogenase (LDH) were prognostic variables with statistical significance (P < 0.05). The patients were classified into three groups of patients according to how many of these 5 risk factors were present: 0-1, 2, or 3-5 risk factors. The median OS of the 3 groups of patients were 5.0, 3.3, and 2.5 months, respectively, with a notable statistical significance (P < 0.0001). CONCLUSIONS: KPS<80, ascites, cigarette smoking, primary tumor size≥5 cm, and LDH≥250U/L are effective predictive factors of poor prognosis for patients with PACLM. The stratification of treatment outcome groups based on these factors facilitates evaluation of individual prognosis and can guide clinical decisions.

Factors Affecting the Dissolution of Indomethacin Solid Dispersions.

The aim of this study was to investigate the influence of factors such as carrier type, drug/carrier ratio, binary carriers, and preparation method on the dissolution of an insoluble drug, indomethacin (IM), under supersaturation conditions. Using a solvent evaporation (SE) method, poloxamer 188 and PVP K30 showed better dissolution among the selected carriers. Furthermore, as the ratio of carriers increased (drug/carrier ratio from 1:0.5 to 1:2), the dissolution rate increased especially in almost two times poloxamer 188 solid dispersions (SDs), while the reverse results were observed for PVP K30 SDs. For the binary carrier SD, a lower dissolution was found. Under hot melt extrusion (HME), the dissolution of poloxamer 188 SD and PVP K30 SD was 0.83- and 0.94-folds lower than that using SE, respectively, while the binary carrier SD showed the best dissolution. For poloxamer 188 SDs, the drug's crystal form changed when using SE, while no crystal form change was observed using HME. IM was amorphous in PVP K30 SDs prepared by both methods. For binary carrier systems, amorphous and crystalline drugs coexisted in SD using SE, and negligible amorphous IM was in SD using HME. This study indicated that a higher amorphous proportion in SD did not correlate with higher dissolution rate, and other factors, such as carrier type, particle size, and density, were also critical.

Geraniin exerts cytoprotective effect against cellular oxidative stress by upregulation of Nrf2-mediated antioxidant enzyme expression via PI3K/AKT and ERK1/2 pathway.

BACKGROUND: Geraniin, an active compound with remarkable antioxidant activity, was isolated from Geranium sibiricum. The present study aimed to investigate whether geraniin has the ability to activate Nrf2, induce antioxidant enzyme expression and protect cells from oxidative damage. METHODS: The cells were pretreated with geraniin for 24h and exposed to hydrogen peroxide (H2O2) for 4h. Intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential and apoptosis were measured. We also investigated intracellular glutathione (GSH) levels and changes in nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling cascade in cells treated with geraniin. RESULTS: We investigated the protective effects of geraniin against H2O2-induced apoptosis in HepG2 cells. Geraniin significantly reduced H2O2-induced oxidative damage in a dose dependent manner. Further, geraniin induced the expression of heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO1) and level of glutathione (GSH) in a concentration- and time-dependent manner, and increased Nrf2 nuclear translocation. The Nrf2-related cytoprotective effects of geraniin were PI3K/AKT and extracellular signal-regulated protein kinase1/2 (ERK1/2) pathway-dependent. However, inhibitors of PI3K/AKT and ERK1/2 (LY294002 or U0126) not only suppressed geraniin-induced nuclear translocation of Nrf2 but also abolished the expression of HO-1, NQO1 and GSH. CONCLUSIONS: These results demonstrated that geraniin induced Nrf2-mediated expression of antioxidant enzymes HO-1 and NQO1, presumably via PI3K/AKT and ERK1/2 signaling pathways, thereby protecting cells from H2O2-induced oxidative cell death. GENERAL SIGNIFICANCE: Geraniin, at least in part, offers an antioxidant defense capacity to protect cells from the oxidative stress-related diseases.