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There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia (CNS-ALL). Integrin α6 is considered a potential target for CNS-ALL diagnosis and therapy because of its role in promoting CNS-ALL disease progression. The targeted peptide D(RWYD) (abbreviated RD), with nanomolar affinity to integrin α6 was identified by peptide scanning techniques such as alanine scanning, truncation, and D-substitution. Herein, we developed a therapeutic nanoparticle based on the integrin α6-targeted peptide for treating CNS-ALL. The self-assembled proapoptotic nanopeptide D(RWYD)-D(KLAKLAK)2-GD(FFY) (abbreviated RD-KLA-Gffy) contains the integrin α6-targeted peptide RD, the well-known proapoptotic peptide D(KLAKLAK)2 (abbreviated KLA), and the self-assembling tetrapeptide GD(FFY) (abbreviated Gffy). The functional mechanism of RD-KLA-Gffy is clarified using different experiments. Our results demonstrate that RD-KLA-Gffy is highly enriched in CNS-ALL lesions and induces tumor cell apoptosis, thus reducing CNS-ALL disease burden and prolonging the survival of CNS-ALL mice without obvious toxicity. Moreover, the combined use of RD-KLA-Gffy and methotrexate (MTX) shows a potent antitumor effect in treating CNS-ALL, indicating that RD-KLA-Gffy plays an important role in suppressing CNS-ALL progression either as a single agent or in combination with MTX, which shows promise for application in CNS-ALL therapy.

Background/Aims: Several pathological classification systems were commonly used in clinical practice to predict the prognosis of IgA nephropathy (IgAN). However, how prognostic value differs between these systems is unclear. The aim of this study was to compare the Lee grade, the Oxford classification, and the Haas classification and to find a simplified classification. Methods: We retrospectively analyzed IgAN cases diagnosed between January 2002 and December 2007. The endpoints were progression to end-stage renal disease (ESRD) or a ≥50% decline in estimated glomerular filtration rate (eGFR). The predictive capabilities were evaluated by comparing the ability of discrimination (continuous net reclassification) and calibration (Akaike information criterion [AIC]). Results: A total of 412 IgAN patients were included in the study. The average follow-up period was 80.62 ± 23.63 months. A total of 44 (10.68%) patients progressed to ESRD, and 70 (16.99%) patients showed a ≥50% decline in eGFR. All multivariate Cox regression models had limited power for high AIC values. The prognostic values of the Lee grade and the Oxford classification were higher than those of models containing only established baseline clinical indicators for progression to ESRD or a ≥50% decline in eGFR (Lee grade 0.50, 95% CI 0.21–0.74; Oxford classification 0.48, 95% CI 0.28–0.71). The prognostic value of the Haas classification was lower than that of the other pathological classification systems for progression to ESRD or a ≥50% decline in eGFR (Lee grade 0.53, 95% CI 0.23–0.92; Oxford classification 0.59, 95% CI 0.10–0.74). The prognostic value of hierarchical classification (Beijing classification) using M and T lesion was similar to the Oxford classification. Conclusions: Both the Lee grade and the Oxford classification showed incremental prognostic values beyond established baseline clinical indicators. The Haas classification was slightly inferior to the Lee grade and the Oxford classification. The hierarchical classification (Beijing classification) using less pathological parameters does not lose predictive efficiency.

Background: The efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for immunoglobulin A nephropathy (IgAN) are unclear. This study was designed to evaluate the efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for IgAN. Methods: It is a multicenter, prospective, double-dummy randomized controlled trial. Primary IgAN patients were recruited in 13 renal units across Beijing, China, from July 2010 to June 2012. After a 4-week telmisartan (80 mg/d) wash-in, 400 patients continuing on 80 mg/d telmisartan were randomly assigned to additionally receive placebo (Group A), 50 mg/d clopidogrel (Group B), 20 mg/d leflunomide (Group C), or 50 mg/d clopidogrel and 20 mg/d leflunomide (Group D). The 24-week intervention was completed by 360 patients. The primary endpoint was change in 24-h proteinuria at 24 weeks. A linear mixed-effect model was used to analyze the changes at 4, 12, and 24 weeks. Generalized estimating equations were used to evaluate changes in hematuria grade. This trial was registered at the Chinese Clinical Trial Registry. Results: The effects of telmisartan combined with leflunomide on changes in proteinuria (0.36 [95% confidence interval (CI) 0.18–0.55] g/d, P < 0.001), in serum uric acid (76.96 [95% CI 57.44–96.49] μmol/L, P < 0.001), in serum creatinine (9.49 [95% CI 6.54–12.44] μmol/L, P < 0.001), and in estimated glomerular filtration rate (−6.72 [95% CI−9.46 to −3.98] ml·min−1·1.73 m−2, P < 0.001) were statistically significant, whereas they were not statistically significant on changes in systolic and diastolic blood pressure and weight (P > 0.05). Telmisartan combined with clopidogrel had no statistical effect on any outcome, and there was no interaction between the interventions. No obvious adverse reactions were observed. Conclusions: Telmisartan combined with leflunomide, not clopidogrel, is safe and effective for decreasing proteinuria in certain IgAN patients. Trial Registration: chictr.org.cn, ChiCTR-TRC-10000776; http://www.chictr.org.cn/showproj.aspx?proj=8760.

BACKGROUND: Internal medicine includes several subspecialties. This study aimed to describe change trend of impact factors in different subspecialties of internal medicine during the past 12 years, as well as the developmental differences among each subspecialty, and the possible influencing factors behind these changes and differences. METHODS: Nine subspecialties of internal medicine were chosen for comparison. All data were collected from the Science Citation Index Expanded and Journal Citation Reports database. RESULTS: (1) Journal numbers in nine subspecialties increased significantly from 1998 to 2010, with an average increment of 80.23%, in which cardiac and cardiovascular system diseases increased 131.2% rank the first; hematology increased 45% rank the least. (2) Impact Factor in subspecialties of infectious disease, cardiac and cardiovascular system diseases, gastroenterology and hepatology, hematology, endocrinology and metabolism increased significantly (p6), hematology had the maximum proportion of 10%, nephrology and respiratory system disease had the minimum of 4%. Among the journal with low impact factor (IF

In the title compound, C20H13NO, the indene ring is disordered over two sites with an occupancy ratio of 0.557 (2):0.443 (2). Both disordered components of indene are nearly perpendicular to the naphthalene ring system, making dihedral angles of 90.9 (2) and 85.0 (5)°. The five-membered ring of the 1H-pyrrol-2(3H)-one adopts an envelope conformation with the spiro C atom at the flap position. Intermolecular classical N—H...O and weak C—H...O hydrogen bonding is present in the crystal structure.

Aerobic growth conditions have affected anaerobic succinate production in two-stage fermentation by Escherichia coli AFP111 with knockouts in rpoS, pflAB, idhA and ptsG genes. Enzymes involved in the reductive arm of the tricarboxylic acid cycle and the glyoxylate shunt have displayed elevated activities at a low cell growth rate limited by glucose, which have provided AFP111 with intracellular redox balance and increased succinic acid yield and productivity.

Background: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. The clinical spectrum of IgAN varies from minor urinary abnormalities to rapidly progressive renal failure. Evaluation of the disease by repeated renal biopsy is not practical due to its invasive procedure. Urinary sediment miRNAs promise to serve as non-invasive biomarkers to assess kidney injury of IgAN.Methods: Fifty two biopsy-proven IgAN patients and twenty five healthy controls were enrolled in the study. Urinary sediment miRNAs were extracted. Expressions of miR-34a, miR-205, miR-21, miR-146a and miR-155 were quantified by real-time quantitative polymerase chain reaction (RT-QPCR). The receiver operating characteristic (ROC) curve was used to investigate the value of the miRNAs for predicting diagnosis of IgAN and evaluating histopathological injury. The patients were treated according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and followed up. The roles of miRNAs in reflecting therapeutic efficacy and disease progression were analyzed.Results: 1. The IgAN group had significantly lower urinary miR-34a, miR-205, and miR-155, but higher miR-21 levels than controls. The ROC revealed that urinary miR-34a ≤ 0.047, miR-205 ≤ 0.209, miR-21 ≥ 0.461 and miR-155 ≤ 0.002 could distinguish patients with IgAN from healthy ones. In addition, miR-205 ≤ 0.125 and miR-21 ≥ 0.891 can distinguish IgAN patients with severe tubular atrophy/interstitial fibrosis from those with mild tubular atrophy/interstitial fibrosis. 2. After a mean 15.19 months follow-up, the reduction of proteinuria (g/24 h/year) was positively correlated with baseline urinary miR-21 and inversely correlated with miR-205. The levels of baseline eGFR and miR-205 in the complete remission group were significantly higher than non-complete remission group (p < 0.001; p = 0.018), while proteinuria, miR-21 and miR-146a were lower than non-complete remission group (p = 0.002; p = 0.021; p = 0.009). But multivariate analysis revealed that only baseline eGFR correlated with the remission of IgAN (p = 0.001, OR = 1.042).Conclusions: The levels of some urinary sediment miRNAs, especially baseline miR-21 and miR-205, may be used as potential prognostic markers for evaluating the tubulointerstitial damage of IgAN. Furthermore, baseline levels of urinary miRNAs may be predictors of therapeutic efficacy and disease progression. [ABSTRACT FROM AUTHOR]

Background: IgA nephropathy is the most common progressive glomerular disease to end stage renal failure worldwide. Calcineurin inhibitors (CNIs) is a selective immunosuppressant widely used in organ transplantation. The efficacy and safety of calcineurin inhibitors for the treatment of IgA nephropathy remain uncertain.Methods: We performed a systematic literature search using the PubMed, Embase, Science Citation Index, Ovid evidence-based medicine, Chinese Biomedical Literature (CBM) and Chinese science and technology periodicals (CNKI, VIP, and Wan Fang) for randomized, controlled trials of CNIs therapy of IgA nephropathy. Complete remission rate (CR) was defined as proteinuria less than 0.5 or 0.3 g/d. Partial remission rate (PR) was defined as proteinuria reduced to at least half of the baseline measurement and an absolute value of >0.5 or 0.3 g/d.Results: Seven relevant trials were conducted with 374 patients enrolled. CNIs plus medium/low-dose steroid had a higher CR (RR = 2.51 [95% CI,1.25 to 5.04], P = 0.02) compared to therapy with steroid alone or placebo, but were not significant on PR (RR = 0.87 [95% CI,0.32 to 2.38]; P = 0.78). Also, significant alterations were observed in proteinuria (weighted mean difference, -0.46 g/d,[95% CI:-0.55 to -0.24], P < 0.01) with no differences were found in serum creatinine (SCr) (weighted mean difference, 0.57,95% CI:-4.05 to 5.19; P = 0.78) and estimated glomerular filtration rate (eGFR) (weighted mean difference, 1.13,95% CI:-4.05 to 6.32; P = 0.34) level between the two groups. CNI therapy was associated with an increased risk for adverse events (RR = 2.21,95% CI:1.52 to 3.21, P < 0.01), such as gastrointestinal and neurological symptoms or hirsutism.Conclusions: CNIs might provide renal protection in patients with IgAN, but at an increased risk of adverse events. Reliably defining the efficacy and safety of CNIs in IgAN requires a high-quality trial with a large sample size. [ABSTRACT FROM AUTHOR]

The morphology of the reproductive systems and the coupling mechanism between the male and the female genitalia during copulation in Dioryctria rubella Hampson are described. Differing from those in other genera of Phycitinae moths, the corpus bursae possesses a well-developed signum, and the seminal duct does not exhibit a bulla seminalis, instead arising from the ventral surface of the corpus bursae. The ultrastructural observation shows that the spines on the inner surface of the ductus bursae and the cervix bursa are complementary to that of cornuti on the outer surface of vesica in position and direction, which elucidates the matching mechanism between the ductus bursae and the vesica. The male possesses well-developed scale brushes, which consist of six pairs of overlapped structures. Finally, the morphological differences of scale brushes between D. rubella and other Dioryctria species and related genera, and their function during copulation are discussed. [ABSTRACT FROM AUTHOR]

Escherichia coli AFP111, a pflB, ldhA, ptsG triple mutant of E. coli W1485, can be recovered for additional succinate production in fresh medium after two-stage fermentation (an aerobic growth stage followed by an anaerobic production stage). However, the specific productivity is lower than that of two-stage fermentation. In this study, three strategies were compared for reusing the cells. It was found when cells were aerobically cultivated at the end of two-stage fermentation without supplementing any carbon source, metabolites (mainly succinate and acetate) could be consumed. As a result, enzyme activities involved in the reductive arm of tricarboxylic acid cycle and the glyoxylate shunt were enhanced, yielding a succinate specific productivity above $$ 1 2 5\;{\text{mg}}\;{\text{g}}_{\rm DCW}^{ - 1} \,{\text{h}}^{ - 1} $$ and a mass yield above 0.90 g g in the subsequent anaerobic fermentation. In addition, the intracellular NADH of cells subjected to aerobic cultivation with metabolites increased by more than 3.6 times and the ratio of NADH to NAD increased from 0.4 to 1.3, which were both favorable for driving the TCA branch to succinate. [ABSTRACT FROM AUTHOR]

Escherichia coli AFP111 cells recovered from spent two-stage fermentation broth were investigated for additional production of succinic acid under anaerobic conditions. Recovered cells produced succinic acid in an aqueous environment with no nutrient supplementation except for glucose and MgCO. In addition, initial glucose concentration and cell density had a significant influence on succinic acid mass yield and productivity. Although the final concentration of succinic acid from recovered cells was lower than from two-stage fermentation, an average succinic acid mass yield of 0.85 g/g was achieved with an average productivity of 1.81 g/l h after three rounds of recycling, which was comparable to two-stage fermentation. These results suggested that recovered cells might be reused for the efficient production of succinic acid. [ABSTRACT FROM AUTHOR]

A series of new (CH2)n-bridged diimidazolium (or dibenzimidazolium) salts (n= 3, 4 and 5) were prepared. Reaction of the diimidazolium (or dibenzimidazolium) salts with Ag2O or Ag2CO3leads to eight macrocyclic dinuclear N-heterocyclic carbene (NHC) silver(i) complexes, [{1,1′-dialkyl-3,3′-(CH2)n-diimidazol-2-ylidene}2Ag2]·2Z (2a: alkyl = Et, n= 3, Z= 1/2[Ag2Br4], 2b: alkyl = PhCH2, n= 3, Z= PF6; 2c: alkyl = Et, n= 4, Z= PF6; 2d: alkyl = PhCH2, n= 4, Z= PF6; 2e: alkyl = Et, n= 5, Z= PF6; 2f: alkyl = PhCH2, n= 5, Z= PF6) and [{1,1′-dialkyl-3,3′-(CH2)3-dibenzimidazol-2-ylidene}2Ag2]·2PF6(2g: alkyl = nBu; 2h: alkyl = PhCH2). In these complexes, each cationic macrocycle is composed of two silver(i) atoms and two (CH2)n-bridged dicarbene ligands. The 2+ charge of each cation is balanced by different anions ([Ag2Br4]2−for 2aand 2PF6−for 2b–2h). Interestingly, these cationic macrocycles of 2a–2hadopt four diverse conformations (i.e., trans, zigzag, helical and calix-like conformations) due to the different arrangements of bridging (CH2)n-chains in the solid state. Additionally, analyses of the crystal packings of 2a–2hreveal that 2D supramolecular layers of 2a, 2c, 2dand 2f–2hand 1D supramolecular chains of 2band 2eare formed viaintermolecular weak interactions, including π–π stacking interactions, hydrogen bonds and weak AgF bonds. [ABSTRACT FROM AUTHOR]

Seminal amyloid fibrils are made up of naturally occurring peptide fragments and are key targets for the development of combination microbicides or antiviral drugs. Previously, we reported that the polysulfonic compound ADS-J1 is a potential candidate microbicide that not only inhibits HIV-1 entry, but also seminal fibrils. However, the carcinogenic azo moieties in ADS-J1 preclude its clinical application. Here, we screened several ADS-J1-like analogs and found that the antiparasitic drug suramin most potently inhibited seminal amyloid fibrils. Using various biochemical methods, including Congo red staining, CD analysis, transmission EM, viral infection assays, surface plasmon resonance imaging, and molecular dynamics simulations, we investigated suramin's inhibitory effects and its putative mechanism of action. We found that by forming a multivalent interaction, suramin binds to proteolytic peptides and mature fibrils, thereby inhibiting seminal fibril formation and blocking fibril-mediated enhancement of viral infection. Of note, suramin exhibited potent anti-HIV activities, and combining suramin with several antiretroviral drugs produced synergistic effects against HIV-1 in semen. Suramin also displayed a good safety profile for vaginal application. Moreover, suramin inhibited the semen-derived enhancer of viral infection (SEVI)/semen-mediated enhancement of HIV-1 transcytosis through genital epithelial cells and the subsequent infection of target cells. Collectively, suramin has great potential for further development as a combination microbicide to reduce the spread of the AIDS pandemic by targeting both viral and host factors involved in HIV-1 sexual transmission. [ABSTRACT FROM AUTHOR]

The persistence of HIV in resting memory CD4 T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. Proteasome inhibitors (PIs) were previously reported as latency reversing agents (LRAs) but the mechanism underlying this function is yet unclear. Here we demonstrate that PIs reactivate latent HIV ex vivo without global T cell activation, and may facilitate host innate immune responses. Mechanistically, latent HIV reactivation induced by PIs is mediated by heat shock factor 1 (HSF1) via the recruitment of the heat shock protein (HSP) 90-positive transcriptional elongation factor b (p-TEFb) complex. Specifically, HSP90 downstream HSF1 gives positive feedback to the reactivation process through binding to cyclin-dependent kinase 9 (CDK9) and preventing it from undergoing degradation by the proteasome. Overall, these findings suggest proteasome inhibitors as potential latency reversing agents. In addition, HSF1/HSP90 involved in HIV transcription elongation, may serve as therapeutic targets in HIV eradication. [ABSTRACT FROM AUTHOR]

Two contrasting intrusive suites have been identified from the northern margin of the North China craton: a Late Carboniferous diorite-granodiorite suite mainly made up of quartz diorite, diorite, granodiorite, tonalite, and hornblende gabbro, and a Late Permian-- Middle Triassic suite of granitoid intrusions consisting of monzogranite, syenogranite, and quartz monzonite. Plutons from the Late Carboniferous suite exhibit variable SiO2 contents and calc-alkaline or high-K calc-alkaline, metaluminous geochemical features. Most have low negative whole-rock εNd(T) values (where T is the crystallization age) of -17.1 to -11.5 and zircon εHf(T) values of -38.3 to -11.2, indicating that they were derived mainly from anatectic melting of the ancient lower crust with some involvement of mantle materials. However, an older pluton in the suite exhibits higher εNd(T) values of -11.5 to -9.9, Nd model ages of 1.82-1.64 Ga, lower initial 87Sr/86Sr ratios of 0.7046-0.7048, and it contains some zircon grains that are characterized by high negative to positive zircon εHf(T) values of -8.7 to 1.2, indicating strong involvement of juvenile materials derived from the lithospheric mantle. The Late Carboniferous plutons are interpreted as subduction- related and to have been emplaced in an Andean-style continental-margin arc during the southward subduction of the paleo-Asian oceanic plate beneath the North China craton. Rocks from the Late Permian-Middle Triassic intrusive suite display geochemical signatures ranging from highly fractionated I-type to A-type. They exhibit higher zircon εHf(T) values of -14.9 to -6.7, whole-rock εNd(T) values of -10.6 to -8.8, and younger Hf and Nd model ages than most of the Late Carboniferous plutons, indicating that they could have been produced by extreme fractional crystallization of hybrid magmas resulted from mixing of coeval mantle- and crust-derived melts. They are interpreted as postcollisional/ postorogenic granitoids linked to lithospheric extension and asthenosphere upwelling due to slab break-off and subsequent sinking after final collision and suturing of the Mongolian arc terranes with the North China craton. These two contrasting intrusive suites suggest that the final closure of the paleo--Asian Ocean and collision between the Mongolian arc terranes and the North China craton occurred during the Late Permian, and these events were followed by postcollisional/ postorogenic extension, large-volume magmatism, and significant continental growth. No significant syncollisional crustal thickening, high-pressure metamorphism, or S-type granitoid magmatism occurred during the collision process. [ABSTRACT FROM AUTHOR]