Dynamic change of oligopeptides and free amino acids composition in five types of tea with different fermentation degree processed from the same batch of fresh tea (Camelilia Sinensis. L.) leaves.

Our previous studies have confirmed oligopeptides could be meaningful to tea taste and biofunction. As the total content of oligopeptide among different tea types were varied. It is a natural speculation that certain tea processing step could be vital for oligopeptides enrichment. In current study, five types of traditional Chinese tea were produced from the same batch of fresh leaves. Step processing samples were acquired through which to profile the oligopeptides and free amio acids composition change during tea processed. As a result, firstly, withering was the vital step for oligopeptide enrichment, followed by fermentation, yellowing and drying. Secondly, as the enrichment of oligopeptides was often accompanied by the increase of protein amino acids, suggesting certain proteins degradation in fresh leaves could be the main source of oligopeptides. Thirdly, a total of 166 abundant oligopeptides were screened out, through which 14 high degradation protein were also located by protomic approaching.

Difference in liver injury induced by dictamnine between males and females: based on untargeted metabolomics / 中国中药杂志

In recent years, reports of adverse reactions related to traditional Chinese medicine(TCM) have been on the rise, especially some traditionally considered "non-toxic" TCM(such as Dictamni Cortex). This has aroused the concern of scholars. This study aims to explore the metabolomic mechanism underlying the difference in liver injury induced by dictamnine between males and females through the experiment on 4-week-old mice. The results showed that the serum biochemical indexes of liver function and organ coefficients were significantly increased by dictamnine(P<0.05), and hepatic alveolar steatosis was mainly observed in female mice. However, no histopathological changes were observed in the male mice. Furthermore, a total of 48 differential metabolites(such as tryptophan, corticosterone, and indole) related to the difference in liver injury between males and females were screened out by untargeted metabolomics and multivariate statistical analysis. According to the receiver operating characteristic(ROC) curve, 14 metabolites were highly correlated with the difference. Finally, pathway enrichment analysis indicated that disorders of metabolic pathways, such as tryptophan metabolism, steroid hormone biosynthesis, and ferroptosis(linoleic acid metabolism and arachidonic acid metabolism), may be the potential mechanism of the difference. Liver injury induced by dictamnine is significantly different between males and females, which may be caused by the disorders of tryptophan metabolism, steroid hormone biosynthesis, and ferroptosis pathways.

Quantification, identification and comparison of oligopeptides on five tea categories with different fermentation degree by Kjeldahl method and ultra-high performance liquid chromatography coupled with quadrupole-orbitrap ultra-high resolution mass spectrometry.

Peptides with different lengths or amino sequences could have specific tastes or bio-activities. So far, either the quantity or pattern differences of peptide among various of teas were unknown. Here, firstly, we developed a method for tea oligopeptide quantification and made comparison of their contents. Secondly, we applied ultra-high performance liquid chromatography coupled with quadrupole-orbitrap ultra-high resolution mass spectrometry (UHPLC-Quadrupole-Orbitrap-UHRMS) to sequence oligopeptides. As a result, the total amount of oligopeptides in white tea and dark tea were higher, followed by black tea and green tea, finally with oolong tea. It suggested that withering which undergoes with endogenous protease and post-fermented that undergoes with a participation of exotic micro-organisms were key in oligopeptide enrichment. Thirdly, a total of 902 abundant identified peptides, most of which were tripeptide, tetrapeptide, pentapeptide, and hexapeptide were screened against several existing peptide databases. There were a series of taste peptides and bio-active peptides existing.

Large-scale phenotypic drug screen identifies neuroprotectants in zebrafish and mouse models of retinitis pigmentosa.

Retinitis pigmentosa (RP) and associated inherited retinal diseases (IRDs) are caused by rod photoreceptor degeneration, necessitating therapeutics promoting rod photoreceptor survival. To address this, we tested compounds for neuroprotective effects in multiple zebrafish and mouse RP models, reasoning drugs effective across species and/or independent of disease mutation may translate better clinically. We first performed a large-scale phenotypic drug screen for compounds promoting rod cell survival in a larval zebrafish model of inducible RP. We tested 2934 compounds, mostly human-approved drugs, across six concentrations, resulting in 113 compounds being identified as hits. Secondary tests of 42 high-priority hits confirmed eleven lead candidates. Leads were then evaluated in a series of mouse RP models in an effort to identify compounds effective across species and RP models, that is, potential pan-disease therapeutics. Nine of 11 leads exhibited neuroprotective effects in mouse primary photoreceptor cultures, and three promoted photoreceptor survival in mouse rd1 retinal explants. Both shared and complementary mechanisms of action were implicated across leads. Shared target tests implicated parp1-dependent cell death in our zebrafish RP model. Complementation tests revealed enhanced and additive/synergistic neuroprotective effects of paired drug combinations in mouse photoreceptor cultures and zebrafish, respectively. These results highlight the value of cross-species/multi-model phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for RP patients.

Photoreceptors are the cells responsible for vision. They are part of the retina: the light-sensing tissue at the back of the eye. They come in two types: rods and cones. Rods specialise in night vision, while cones specialise in daytime colour vision. The death of these cells can cause a disease, called retinitis pigmentosa, that leads to vision loss. Symptoms often start in childhood with a gradual loss of night vision. Later on, loss of cone photoreceptors can lead to total blindness. Unfortunately, there are no treatments available that protect photoreceptor cells from dying. Research has identified drugs that can protect photoreceptors in animal models, but these drugs have failed in humans. The classic way to look for new treatments is to find drugs that target molecules implicated in a disease, and then test them to see if they are effective. Unfortunately, many drugs identified in this way fail in later stages of testing, either because they are ineffective, or because they have unacceptable side effects. One way to reverse this trend is to first test whether a drug is effective at curing a disease in animals, and later determining what it does at a molecular level. This could reveal whether drugs can protect photoreceptors before research to discover their molecular targets begins. Tests like this across different species could maximise the chances of finding a drug that works in humans, because if a drug works in several species, it is more likely to have shared target molecules across species. Applying this reasoning, Zhang et al. tested around 3,000 drug candidates for treating retinitis pigmentosa in a strain of zebrafish that undergoes photoreceptor degeneration similar to the human disease. Most of these drug candidates already have approval for use in humans, meaning that if they were found to be effective for treating retinitis pigmentosa, they could be fast-tracked for use in people. Zhang et al. found three compounds that helped photoreceptors survive both in zebrafish and in retinas grown in the laboratory derived from a mouse strain with degeneration similar to retinitis pigmentosa. Tests to find out how these three compounds worked at the molecular level revealed that they interfered with a protein that can trigger cell death. The tests also found other promising compounds, many of which offered increased protection when combined in pairs. Worldwide there are between 1.5 and 2.5 million people with retinitis pigmentosa. With this disease, loss of vision happens slowly, so identifying drugs that could slow or stop the process could help many people. These results suggest that placing animal testing earlier in the drug discovery process could complement traditional target-based methods. The compounds identified here, and the information about how they work, could expand potential treatment research. The next step in this research is to test whether the drugs identified by Zhang et al. protect mammals other than mice from the degeneration seen in retinitis pigmentosa.

Control of neurogenic competence in mammalian hypothalamic tanycytes.

Hypothalamic tanycytes, radial glial cells that share many features with neuronal progenitors, can generate small numbers of neurons in the postnatal hypothalamus, but the identity of these neurons and the molecular mechanisms that control tanycyte-derived neurogenesis are unknown. In this study, we show that tanycyte-specific disruption of the NFI family of transcription factors (Nfia/b/x) robustly stimulates tanycyte proliferation and tanycyte-derived neurogenesis. Single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis reveals that NFI (nuclear factor I) factors repress Sonic hedgehog (Shh) and Wnt signaling in tanycytes and modulation of these pathways blocks proliferation and tanycyte-derived neurogenesis in Nfia/b/x-deficient mice. Nfia/b/x-deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, fire action potentials, receive synaptic inputs, and selectively respond to changes in internal states. These findings identify molecular mechanisms that control tanycyte-derived neurogenesis, which can potentially be targeted to selectively remodel the hypothalamic neural circuitry that controls homeostatic physiological processes.

Single-cell infrared phenomics: phenotypic screening with infrared microspectroscopy.

We conceptually demonstrate single-cell infrared phenomics as a novel strategy of phenotypic screening with infrared microspectroscopy. Based on this development, the cancer cell HepG2 glycocalyx was first identified as a potential target of protopanaxadiol, an herbal medicine. These findings provide a powerful tool to accurately evaluate the cell stress response and to largely expand the phenotypic screening toolkit for drug discovery.

PanoView: An iterative clustering method for single-cell RNA sequencing data.

Single-cell RNA-sequencing (scRNA-seq) provides new opportunities to gain a mechanistic understanding of many biological processes. Current approaches for single cell clustering are often sensitive to the input parameters and have difficulty dealing with cell types with different densities. Here, we present Panoramic View (PanoView), an iterative method integrated with a novel density-based clustering, Ordering Local Maximum by Convex hull (OLMC), that uses a heuristic approach to estimate the required parameters based on the input data structures. In each iteration, PanoView will identify the most confident cell clusters and repeat the clustering with the remaining cells in a new PCA space. Without adjusting any parameter in PanoView, we demonstrated that PanoView was able to detect major and rare cell types simultaneously and outperformed other existing methods in both simulated datasets and published single-cell RNA-sequencing datasets. Finally, we conducted scRNA-Seq analysis of embryonic mouse hypothalamus, and PanoView was able to reveal known cell types and several rare cell subpopulations.

Identification and comparison of oligopeptides during withering process of White tea by ultra-high pressure liquid chromatography coupled with quadrupole-orbitrap ultra-high resolution mass spectrometry.

Peptides could have specific tastes or bioactivities depending on the length and sequence of amino acids. Till date it remains unknown what peptides are formed during the white tea manufacturing process and whether they contribute to the flavor or bio-activities of white tea. As a first step to address these questions, we applied ultra-high pressure liquid chromatography coupled with quadrupole-orbitrap ultra-high resolution mass spectrometry (UPLC-Quadrupole-Orbitrap-UHRMS) to monitor peptides dynamic changes during the withering process. A total of 196 abundant peptides were identified. Most of them were oligopeptides within a molecular weight of 1000 Da. Four of them were randomly selected, synthesized peptides were applied for further confirmation and quantification. Sequence analysis suggested that some of them were potential taste contributors. Proteinase cleave site analysis identified two separate periods of active proteins degradation at 0-12 h and 30-42 h of the withering processes. Further analysis of cleavage sites also suggested that protein degradation during withering steps were random rather than a stepwise reaction.

Hydrophilic interaction liquid chromatography coupled with quadrupole-orbitrap ultra high resolution mass spectrometry to quantitate nucleobases, nucleosides, and nucleotides during white tea withering process.

Nucleotides, nucleosides, and nucleobases are important bioactive compounds. Recent studies suggested that they possess taste activity. However, it remains unknown about their presence in white tea and how they change during white tea manufacture. Here, we first established method based on hydrophilic interaction liquid chromatography coupled with quadrupole-orbitrap ultra high resolution mass spectrometry (HILIC-Quadrupole-Orbitrap-UHRMS) platform, then applied it to study the dynamic changes of nucleotides, nucleosides, and nucleobases during white tea withering process. Five compounds, including adenosine 5'-monophosphate monohydrate (AMP), guanosine 5'-monophosphate disodium salt hydrate (GMP), adenosine, cytidine, thymine and uracil, were detected from withering samples. They showed a general decline trend during white tea withering process, however, considerable amount of them was retained after withering for 48 h except adenosine which was below detection limit after withering for 21 h. This study provided a complete picture about nucleotides, nucleosides and nucleobases changes during white tea withering process.

Foxd1 is required for terminal differentiation of anterior hypothalamic neuronal subtypes.

Although the hypothalamus functions as a master homeostat for many behaviors, little is known about the transcriptional networks that control its development. To investigate this question, we analyzed mice deficient for the Forkhead domain transcription factor Foxd1. Foxd1 is selectively expressed in neuroepithelial cells of the prethalamus and hypothalamus prior to the onset of neurogenesis, and is later restricted to neural progenitors of the prethalamus and anterior hypothalamus. During early stages of neurogenesis, we observed that Foxd1-deficient mice showed reduced expression of Six3 and Vax1 in anterior hypothalamus, but overall patterning of the prethalamus and hypothalamus is unaffected. After neurogenesis is complete, however, a progressive reduction and eventual loss of expression of molecular markers of the suprachiasmatic, paraventricular and periventricular hypothalamic is observed. These findings demonstrate that Foxd1 acts in hypothalamic progenitors to allow sustained expression of a subset of genes selectively expressed in mature neurons of the anterior hypothalamus.

Warming needling combined with decoction for arteriosclerosis obliterans with stasis / 中国针灸

<p><b>OBJECTIVE</b>To observe the effect difference of warming needling combined with decoction and ciloprost for arteriosclerosis obliterans (ASO) with stasis.</p><p><b>METHODS</b>A total of 96 ASO patients with stasis were randomly assigned into a combination group and a western medication group, 48 cases in each group. Anti-hypertension, glucose-lowering and lipid lowering therapies were applied in the two groups. Ciloprost was prescribed orally in the western medication group, twice a day, 100 mg a time. The main acupoints in the combination group were Sanyinjiao (SP 6), Yinlingquan (SP 9), Zusanli (ST 36), Guanyuan (CV 4), and Xuehai (SP 10), matched with Yanglingquan (GB 34) and Weizhong (BL 40). Warming needling was used at Sanyinjiao (SP 6), Zusanli (ST 36), Xuehai (SP 10) and Guanyuan (CV 4), 5 times a week, once a day, 20 min a time. At the same time, self-made decoction was applied in the combination group, 1 dose a day, twice a day. All the treatment was given for continuous 3 courses, 1 month as a course. The indexes were the symptom scores for cool limb skin, sour swelling, numbness, pain, abnormal complexion, ankle brachial index (ABI) and blood biochemical indexes, including fasting blood-glucose (FPG), triacylglycerol (TG), cholesterol total (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), glutamic-pyruvic transaminase (ALT), glutamic-oxalacetic transaminase (AST), serum creatinine (Scr) and blood urea nitrogen (BUN). The adverse reactions were recorded. The clinical effect was evaluated. Two-month follow-up was carried out.</p><p><b>RESULTS</b>After treatment, the symptom scores for cool limb skin, sour swelling, numbness, pain, abnormal complexion and total score decreased in the two groups (all <0.05), with better results in the combination group (all <0.05). The bilateral ABI were higher than those before treatment in the two groups (all <0.05), with better results in the combination group (both <0.05). The FPG, TG, TC, HDL-C, LDL-C, ALT, AST, Scr, BUN before and after treatment had no statistical significance in the two groups (all >0.05). There was no adverse reaction on acupuncture and moxibustion. The total effective rate of the combination group was 95.8% (46/48), which was better than 91.7% (44/48) of the western medication group (<0.05). The recurrence and aggravation rate in the combination group was 8.7% (4/46), which was lower than 18.2% (8/44) in the western medication group (<0.05).</p><p><b>CONCLUSION</b>Warming needling combined with decoction for ASO are better than simple oral ciloprost, with safety.</p>

Study on morphological characteristics and microscopic structure of medicinal organs of Pulsatilla chinensis (Bunge) Regel.

Modern clinical studies have found that Pulsatilla radix contains a variety of active ingredients; however, its medicinal parts and microstructure have been controversial. Based on morphological observation and microscopic identification of different structures, we chose Anhui, Henan, Jilin, and Shanxi Province to study Pulsatilla chinensis (Bunge) Regel populations. We specifically addressed different diameters and anatomical structures of different parts of underground organs. We also found that P. chinensis (Bunge) Regel had a "joint point" structure in its underground organ. Above the "joint point" is the rhizome, below the "joint point" is the root. The main medicinal organ is the rhizome. The protective tissues of the endothelial layer of P. chinensis (Bunge) Regel changed in the process of its development. The protective tissues were replaced by epidermis, cortex, endodermis, and phloem. With the secondary growth, the endothelial cells have been radial division. This study showed that morphology and microscopic identification was an important mean of medicinal material identifications, and it had the characteristics of a convenient, fast, and intuitive method to identify the composition and structural characteristics of P. chinensis (Bunge) Regel medicinal parts.

ARQiv-HTS, a versatile whole-organism screening platform enabling in vivo drug discovery at high-throughput rates.

The zebrafish has emerged as an important model for whole-organism small-molecule screening. However, most zebrafish-based chemical screens have achieved only mid-throughput rates. Here we describe a versatile whole-organism drug discovery platform that can achieve true high-throughput screening (HTS) capacities. This system combines our automated reporter quantification in vivo (ARQiv) system with customized robotics, and is termed 'ARQiv-HTS'. We detail the process of establishing and implementing ARQiv-HTS: (i) assay design and optimization, (ii) calculation of sample size and hit criteria, (iii) large-scale egg production, (iv) automated compound titration, (v) dispensing of embryos into microtiter plates, and (vi) reporter quantification. We also outline what we see as best practice strategies for leveraging the power of ARQiv-HTS for zebrafish-based drug discovery, and address technical challenges of applying zebrafish to large-scale chemical screens. Finally, we provide a detailed protocol for a recently completed inaugural ARQiv-HTS effort, which involved the identification of compounds that elevate insulin reporter activity. Compounds that increased the number of insulin-producing pancreatic beta cells represent potential new therapeutics for diabetic patients. For this effort, individual screening sessions took 1 week to conclude, and sessions were performed iteratively approximately every other day to increase throughput. At the conclusion of the screen, more than a half million drug-treated larvae had been evaluated. Beyond this initial example, however, the ARQiv-HTS platform is adaptable to almost any reporter-based assay designed to evaluate the effects of chemical compounds in living small-animal models. ARQiv-HTS thus enables large-scale whole-organism drug discovery for a variety of model species and from numerous disease-oriented perspectives.

A Screen for Extracellular Signal-Regulated Kinase-Primed Glycogen Synthase Kinase 3 Substrates Identifies the p53 Inhibitor iASPP.

UNLABELLED: The Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein is essential for the replication and maintenance of virus genomes in latently KSHV-infected cells. LANA also drives dysregulated cell growth through a multiplicity of mechanisms that include altering the activity of the cellular kinases extracellular signal-regulated kinase (ERK) and glycogen synthase kinase 3 (GSK-3). To investigate the potential impact of these changes in enzyme activity, we used protein microarrays to identify cell proteins that were phosphorylated by the combination of ERK and GSK-3. The assays identified 58 potential ERK-primed GSK-3 substrates, of which 23 had evidence for in vivo phosphorylation in mass spectrometry databases. Two of these, SMAD4 and iASPP, were selected for further analysis and were confirmed as ERK-primed GSK-3 substrates. Cotransfection experiments revealed that iASPP, but not SMAD4, was targeted for degradation in the presence of GSK-3. iASPP interferes with apoptosis induced by p53 family members. To determine the importance of iASPP to KSHV-infected-cell growth, primary effusion lymphoma (PEL) cells were treated with an iASPP inhibitor in the presence or absence of the MDM2 inhibitor Nutlin-3. Drug inhibition of iASPP activity induced apoptosis in BC3 and BCBL1 PEL cells but did not induce poly(ADP-ribose) polymerase (PARP) cleavage in virus-negative BJAB cells. The effect of iASPP inhibition was additive with that of Nutlin-3. Interfering with iASPP function is therefore another mechanism that can sensitize KSHV-positive PEL cells to cell death. IMPORTANCE: KSHV is associated with several malignancies, including primary effusion lymphoma (PEL). The KSHV-encoded LANA protein is multifunctional and promotes both cell growth and resistance to cell death. LANA is known to activate ERK and limit the activity of another kinase, GSK-3. To discover ways in which LANA manipulation of these two kinases might impact PEL cell survival, we screened a human protein microarray for ERK-primed GSK-3 substrates. One of the proteins identified, iASPP, showed reduced levels in the presence of GSK-3. Further, blocking iASPP activity increased cell death, particularly in p53 wild-type BC3 PEL cells.

Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial.

PURPOSE: This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. PATIENTS AND METHODS: Patients were randomly assigned in a 1:1 ratio to linifanib 17.5 mg once daily or sorafenib 400 mg twice daily. Patients were stratified by region (Outside Asia, Japan, and rest of Asia), Eastern Cooperative Oncology Group performance score (ECOG PS; 0 or 1), vascular invasion or extrahepatic spread (yes or no), and hepatitis B virus (HBV) infection (yes or no). The primary end point of the study was overall survival (OS). Secondary end points were time to progression (TTP) and objective response rate (ORR) per RECIST v1.1. RESULTS: We randomly assigned 1,035 patients (median age, 60 years; Asian, 66.6%; ECOG PS 0, 65.2%; HBV, 49.1%; vascular invasion or extrahepatic spread, 70.1%). Median OS was 9.1 months on the linifanib arm (95% CI, 8.1 to 10.2) and 9.8 months on the sorafenib arm (95% CI, 8.3 to 11.0; hazard ratio [HR], 1.046; 95% CI, 0.896 to 1.221). For prespecified stratification subgroups, OS HRs ranged from 0.793 to 1.119 and the 95% CI contained 1.0. Median TTP was 5.4 months on the linifanib arm (95% CI, 4.2 to 5.6) and 4.0 months on the sorafenib arm (95% CI, 2.8 to 4.2; HR, 0.759; 95% CI, 0.643 to 0.895; P = .001). Best response rate was 13.0% on the linifanib arm versus 6.9% on the sorafenib arm. Grade 3/4 adverse events (AEs); serious AEs; and AEs leading to discontinuation, dose interruption, and reduction were more frequent with linifanib (all P < .001). CONCLUSION: Linifanib and sorafenib had similar OS in advanced HCC. Predefined superiority and noninferiority OS boundaries were not met for linifanib and the study failed to meet the primary end point. TTP and ORR favored linifanib; safety results favored sorafenib.

Comparative study on preparation of Polygoni Multiflori Radix based on hepatotoxic bioassay / 中国中药杂志

Toxicity of different processed was evaluated Polygoni Multiflori Radix by determining the hepatotoxic potency for selecting processing technology. Process Polygoni Multiflori Radix using high pressure steamed, Black Bean high pressure steamed, atmospheric steamed for different time. Using normal human hepatocytes (L02) as evaluation model, hepatotoxic potency as index to evaluate hepatotoxic potency of different processed Polygoni Multiflori Radix. Analysis chemical composition of some processed products by UPLC-MS. Hepatotoxic bioassay method cloud evaluate the toxicity of different Polygoni Multiflori Radix samples. Different processing methods can reduce the toxicity of Polygoni Multiflori Radix, high pressure steamed three hours attenuated was better. Different processing methods have different effects on chemical constituents of Polygoni Multiflori Radix. Comparing with crude sample, the contents of gallic acid, 2,3,5,4-tetrahydroxyl diphenylethylene-2-O-glucoside, emodin-8-O-beta glucoside and emodin were decreased in processed products with 3 kinds of different methods. The change trend of 2,3,5,4-tetrahydroxyl diphenylethylene-2-O-glucoside content was similar with hepatotoxic potency. Different processing methods can reduce the toxicity of Polygoni Multiflori Radix. Processing methods and time attenuated obvious impact on toxicity. Recommended further research on the attehuated standard control of Polygoni Multiflori Radix concocted.

Comparison of processed and crude Polygoni Multiflori Radix induced rat liver injury and screening for sensitive indicators / 中国中药杂志

To investigate the difference of liver injury in rats gavaged with crude and processed Polygoni Multiflori Radix. The 75% ethanol extract of crude and processed Polygoni Multiflori Radix (50 g · kg(-1) crude medicine weight/body weight) were continuous oral administered to rats for 6 weeks. Serum biochemical indicators were dynamically detected, the change of liver histopathology was assessed 6 weeks later. Principal component analysis (PCA) was adopted to screen sensitive indicator of the liver damage induced by polygoni multiflori radix. Biochemical tests showed that the crude Polygoni Multiflori Radix group had significant increase of serum ALT, AST, ALP, DBIL and TBIL (P < 0.01 or P < 0.05) and significant decreases of serum IBIL and TBA (P < 0.01 or P < 0.05), while the processed Polygoni Multiflori Radix group showed no obvious changes, compared to the untreated normal group. Histopathologic analysis revealed that crude Polygoni Multiflori Radix group exhibited significant inflammatory cells infiltration in portal area around the blood vessels, tissue destruction and local necrosis of liver cells. There were not obvious pathological changes in processed Polygoni Multiflori Radix group. The results demonstrated that the injury effect of processed Polygoni Multiflori Radix on liver injury of rats was significantly lower than that of unprocessed, and that processing can effectively reduce the hepatotoxicity of Polygoni Multiflori Radix. Traditional transaminase liver function indicators were not sensitive for crude Polygoni Multiflori Radix induced liver damage. The serum content of DBIL and TBIL can reflect the liver damage induced by crude Polygoni Multiflori Radix early and can be sensitive indicators for clinical monitoring the usage of it.

Randomized phase II open-label study of mFOLFOX6 in combination with linifanib or bevacizumab for metastatic colorectal cancer.

BACKGROUND: Although CRC is the third most commonly diagnosed cancer in the United States, second-line CRC treatment is limited. In this trial we examined the efficacy and safety of linifanib, an oral, potent, selective tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor families, with mFOLFOX6, compared with bevacizumab and mFOLFOX6, in previously treated metastatic CRC. PATIENTS AND METHODS: One hundred forty-eight patients with advanced CRC previously treated with fluoropyrimidine or irinotecan received bevacizumab (10 mg/kg, intravenous), low-dose linifanib (7.5 mg), or high-dose linifanib (12.5 mg), with mFOLFOX6. The primary end point was progression-free survival (PFS). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety. RESULTS: No statistically significant differences in PFS occurred between bevacizumab and linifanib doses (low, hazard ratio [HR], 1.453 [95% confidence interval [CI], 0.830-2.539]; high, HR, 1.257 [95% CI, 0.672-2.351]). Median OS values were similar for bevacizumab and high-dose linifanib (bevacizumab, 16.5 months [95% CI, 13.0-not available]; high-dose linifanib, 16.4 months [95% CI, 11.9-21.7]; low-dose linifanib, 12.0 months [95% CI, 10.1-13.0]). ORRs were similar (bevacizumab, 34.7% [95% CI, 21.7-49.6]; low-dose linifanib, 24.0% [95% CI, 13.1-38.2]; high-dose linifanib, 22.4% [95% CI, 11.8-36.6]). Median cycles of 5-fluorouracil were reduced in the linifanib arms, versus the bevacizumab arm. Grade 3/4 adverse event occurrences were more frequent with linifanib. Palmar-plantar erythrodysesthesia, hypothyroidism, and thrombocytopenia were more common with high-dose linifanib than bevacizumab. CONCLUSION: Combining linifanib with mFOLFOX6 as a second-line treatment for metastatic CRC did not improve PFS, radiographic findings, or duration of response versus bevacizumab and mFOLFOX6.

[Retinoblastoma regression patterns and results following chemo reduction and adjuvant therapy].

OBJECTIVE: To evaluate retinoblastoma regression patterns following chemo reduction and adjuvant therapy. METHODS: Retrospective case series. 122 tumors of 47 eyes of 37 patients following chemo reduction and adjuvant therapy between January 2005 and June 2009 in the Eye & ENT hospital of Fudan University. Twenty-seven patients are male, and 10 patients are female. The average age was 22 months. The combined therapy included chemo reduction using vincristine, etoposide, and carboplatin (VEC) combined with local cryotherapy and/or transpupillary thermotherapy (TTT). The average follow-up duration was 32 months ranging from 12 to 60 months. Regression patterns included type 0 (no remnant), type 1 (calcified remnant), type 2 (noncalcified remnant), type 3 (partially calcified remnant), and type 4 (flat scar). Wilcoxon rank sum test was used to test the difference of tumor number between the patients with family history and those without family history. Chi-square test was used to test the difference between the tumor thickness, tumor location and regression patterns. Multivariate logistic regression analysis was used to test the correlation between the regression patterns and age, sex, tumor thickness, tumor location and family history. Statistical significance was assigned at P < 0.05. RESULTS: Forty-seven eyes according to the International Intraocular Retinoblastoma Classification, 20 eyes (42.6%) were group A, 13 eyes (27.6%) group B, 6 eyes (12.8%) group C, 8 eyes (17.0%) group D. Of 122 tumors, the average number of tumors per eye was 2.6. Retinoblastoma regressions were type 0 (n = 3), type 1 (n = 15), type 2 (n = 8), type 3 (n = 25), and type 4 (n = 71). Tumor thickness and tumor location were related to regression patterns. Tumors with an initial thickness of 2 mm or less regressed most often to type 4, and those thicker than 8 mm regressed to type 1 or type 3. Tumors with greater distance from the foveola regressed most often to type 4. The factors predictive of regression pattern type 1 included tumor thickness larger than 8 mm (Z = 3.02, P = 0.003). The factors predictive of regression pattern type 3 included older age, tumor thickness larger than 8 mm and location not in the equator to ora serrata region (Z = 3.98, 2.23, 3.60; P = 0.000, 0.025, 0.000). The factors predictive of regression pattern type 4 included familial hereditary pattern, tumor thickness smaller than 2 mm and location in the equator to ora serrata region. (Z = 4.37, 3.42, 2.42; P = 0.000, 0.000, 0.021). 12 tumors recurred, 9 tumors were type 3 and 3 tumors were type 4. 8 eyes developed 15 new tumors. 5 patients developed new tumors were all younger patients and had familial hereditary history. The average period of recurrence of main tumors and development of new tumors was six months after the end of chemo reduction. CONCLUSIONS: Following chemo reduction, type 3 and type 4 regression patterns were most common. Smaller tumors were usually seen in type 4, and bigger tumors were usually seen in type 1 or type 3. Tumor recurrence was usually found following regression pattern type 3 or type 4. Younger patients and patients with familial hereditary history trend to develop new tumors. Patients accept chemo reduction and adjuvant therapy need close follow-up.

[Clinical therapeutic efficiency of chemoreduction and local therapy for children with retinoblastoma].

OBJECTIVE: To evaluate the therapeutic efficiency of customized combined therapy for retinoblastoma. METHODS: Retrospective case series. Twenty nine patients (40 eyes) with retinoblastoma were accepted customized combined therapy between Jan. 2005 and Dec. 2007 in our hospital. The combined therapy included chemoreduction using vincristine, etoposide, and carboplatin (VEC) combined with local cryotherapy and/or transpupillary thermotherapy (TTT). The average follow-up duration was 38 months and ranging from 12 to 50 months. RESULTS: Twenty five patients had bilateral retinoblastoma, 4 patients had unilateral retinoblastoma. The stages of 40 eyes were classified according to the International Intraocular Retinoblastoma Classification, 14 eyes (35%) were group A, 9 eyes (22.5%) were group B, 4 eyes (10%) were group C, 10 eyes (25%) were group D, and 3 eyes (7.5%) were group E. Seventeen eyes had vitreous and/or subretinal seeds. The overall globe preservation rate was 75% (30/40); and was 100% (14/14) in group A, 100% (9/9) in group B, 75% (3/4) in group C, 40% (4/10) in group D and 0% (0/3) in group E. A progressive decrease of globe preservation rate was observed in eyes with advanced stages. Tumor recurrence was detected in 4 eyes after chemoreduction, leading to the enucleation. Ten eyes were enucleated in the present series, with 1 eye in group C, 6 eyes in group D and 3 eyes in group E. None of 29 patients died during the follow-up. No patients had any serious side effect of chemotherapy such as leukemia. CONCLUSIONS: The customized combined therapy can effectively preserve certain patients' eyeballs and even obtain useful visual function. The International Intraocular Retinoblastoma Classification is useful in the clinical management of retinoblastoma.