Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells.

Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase pump, leading to autophagy induction through the activation of the Ca(2+)/calmodulin-dependent kinase kinase-AMP-activated protein kinase-mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells.

Higher order spin resonances in a 2.1-GeV/c polarized proton beam.

Spin resonances can depolarize or spin flip a polarized beam. We studied 1st and higher order spin resonances with stored 2.1 GeV/c vertically polarized protons. The 1st order vertical (ν(y)) resonance caused almost full spin flip, while some higher order ν(y) resonances caused partial depolarization. The 1st order horizontal (ν(x)) resonance caused almost full depolarization, while some higher order ν(x) resonances again caused partial depolarization. Moreover, a 2nd order ν(x) resonance is about as strong as some 3rd order ν(x) resonances, while some 3rd order ν(y) resonances are much stronger than a 2nd order ν(y) resonance. One thought that ν(y) spin resonances are far stronger than ν(x), and that lower order resonances are stronger than higher order; the data do not support this.

Narrow spin resonance width and spin flip with an rf-bunched deuteron beam.

We used an rf solenoid to study the widths of rf spin resonances with both bunched and unbunched beams of 1.85 GeV/c polarized deuterons stored in the COSY synchrotron. With the unbunched beam at different fixed rf-solenoid frequencies, we observed only partial depolarization near the resonance. However, the bunched beam's polarization was almost fully flipped; moreover, its resonance was much narrower. We then used Chao's recent equations to explain this behavior and to calculate the polarization's dependence on various rf-solenoid and beam parameters. Our data and calculations indicate that a bunched deuteron beam's polarization can behave as if the beam has zero momentum spread.

Experimental test of a new technique to overcome spin-depolarizing resonances.

We recently tested a new spin resonance crossing technique, Kondratenko Crossing (KC), by sweeping an rf-solenoid's frequency through an rf-induced spin resonance with both the KC and traditional fast crossing (FC) patterns. Using both rf bunched and unbunched 1.85 GeV/c polarized deuterons stored in COSY, we varied the parameters of both crossing patterns. Compared to FC with the same crossing speed, KC reduced the depolarization by measured factors of 4.7 +/- 0.3 and 19_{-5};{+12} for unbunched and bunched beams, respectively. This clearly showed the large potential benefit of Kondratenko Crossing over fast crossing.

The impact of caudate lobe involvement after hepatic resection for colorectal metastases.

BACKGROUND: Hepatic resections involving the caudate lobe are technically challenging with results from some centers indicating inferior outcomes. We assessed outcomes following hepatic resection for colorectal metastases involving the caudate lobe in a tertiary care center. METHODS: Operative and oncological data from a prospectively maintained database were analyzed on 687 patients undergoing hepatic resection for colorectal metastases between 1993 and 2006. Patients were analyzed as those with caudate lobe metastases (CLM) and compared with those without caudate lobe involvement (NCLM). RESULTS: Fifty-two of 687 patients had metastases involving the caudate lobe (8%). Patients with caudate lobe involvement were more likely to require an extended hepatic resection (75% vs 27%, P=0.001), perioperative blood transfusion (29% vs 14%, P=0.002), have a positive resection margin (57% vs 32%, P=0.001) and stay longer in hospital (12 vs 8 days, P=0.001). There was no difference in the complication rates (37% vs 29%) or 30-day mortality between the two groups (2% vs 1%). The median disease free (20 months vs 21 months), and cancer specific survival (42 months vs 59 months) were also similar in the CLM and NCLM groups. CONCLUSIONS: Although caudate lobe involvement adds to the technical complexity of hepatic resection, these patients can be offered long term survival, similar to other patients with hepatic metastases from colorectal cancer.

Protective effect of polysaccharides from Angelica sinensis on ulcerative colitis in rats.

Ulcerative colitis (UC) involves the dysregulation of intestinal mucosal immunity and imbalance between the reactive oxygen species (ROS) and the endogenous anti-oxidants. While the protective effects of Angelica sinensis (AS) polysaccharides on neutrophil-dependent gastric mucosal damage have been reported, similar protective effects on UC are still uncertain. Hence our study aimed to investigate the effects of AS polysaccharides on rats with acute UC induced by 2,4-dinitrobenzene sulphonic acid (DNBS) evaluated after 24 h. Intrarectal injection of DNBS significantly reduced the glutathione (GSH) content, increased malondialdehyde concentration and raised the amount of apoptotic cells in colon tissues, which were related to oxidative stress and attenuated by AS polysaccharides pretreatment (5 mg/ml and 10 mg/ml). These findings suggest that oxidative stress and GSH depletion are highly associated with the pathological mechanism of UC, and the protective effects of AS polysaccharides are closely related to the prevention of oxidative stress, which may occur during neutrophil infiltration in the pathological process of UC.

Experimental verification of predicted beam-polarization oscillations near a spin resonance.

The Chao matrix formalism allows analytic calculations of a beam's polarization behavior inside a spin resonance. We recently tested its prediction of polarization oscillations occurring in a stored beam of polarized particles near a spin resonance. Using a 1.85 GeV/c polarized deuteron beam stored in the COoler SYnchrotron, we swept a new rf solenoid's frequency rather rapidly through 400 Hz during 100 ms, while varying the distance between the sweep's end frequency and the central frequency of an rf-induced spin resonance. Our measurements of the deuteron's polarization near and inside the resonance agree with the Chao formalism's predicted oscillations.

Renal transplantation to the ovarian vein: a case report.

Renal failure patients with absent or thrombosed inferior vena cava (IVC) and iliac veins are considered technically unsuitable for transplantation. Occasional cases have been reported in literature of transplant using inferior and superior mesenteric veins. We describe a case in which kidney was transplanted on to an ovarian vein in a young patient who had thrombosed IVC and iliac veins and was previously declared unsuitable for transplantation.

C-reactive protein as a predictor of prognosis following curative resection for colorectal liver metastases.

There is increasing evidence that systemic inflammatory response has a positive correlation with a poorer outcome in patients undergoing resection for solid tumours. The aim of this study was to analyse the impact of an elevated C-reactive protein (CRP), an outcome following curative resection for colorectal liver metastases. One hundred and seventy patients who underwent curative resection for colorectal liver metastases were included in the study. Laboratory measurements of haemoglobin, white cell, platelets, albumin and CRP were taken on the day before surgery. Elevated CRP (>10 mg l(-1)) was present in 54 (31.8%) patients. The median survival of patients with an elevated CRP was 19 months (95% CI 7.5-31.2 months) compared to 42.8 months (95% CI 33.2-52.5 months) for those with a normal CRP, P=0.004. Similarly, when assessing disease-free survival, patients with an elevated CRP had poorer disease-free survival (median of 11.8 months (95% CI 6.4-17.3) compared to median of 15.1 months (95% CI 11.1-19.1)), P=0.043. The result of the study showed that an elevated preoperative CRP is a predictor of poor outcome in patients undergoing curative resection for colorectal liver metastases.

Achieving 99.9% proton spin-flip efficiency at higher energy with a small RF dipole.

We recently used a new ferrite rf dipole to study spin flipping of a 2.1 GeV/c vertically polarized proton beam stored in the COSY Cooler Synchrotron in Jülich, Germany. We swept the rf dipole's frequency through an rf-induced spin resonance to flip the beam's polarization direction. After determining the resonance's frequency, we varied the frequency range, frequency ramp time, and number of flips. At the rf dipole's maximum strength and optimum frequency range and ramp time, we measured a spin-flip efficiency of 99.92+/-0.04%. This result, along with a similar 0.49 GeV/c IUCF result, indicates that, due to the Lorentz invariance of an rf dipole's transverse integralBdl and the weak energy dependence of its spin-resonance strength, an only 35% stronger rf dipole should allow efficient spin flipping in the 100 GeV BNL RHIC Collider or even the 7 TeV CERN Large Hadron Collider.

First spin flipping of a stored spin-1 polarized beam.

We recently studied spin flipping of a 270 MeV vertically polarized deuteron beam stored in the Indiana University Cyclotron Facility Cooler Ring. We adiabatically swept an rf solenoid's frequency through an rf-induced spin resonance and observed its effect on the deuterons' vector and tensor polarizations. After optimizing the resonance crossing rate and maximizing the solenoid's voltage, we measured a vector spin-flip efficiency of 94.2%+/-0.3%. We also found striking behavior of the spin-1 tensor polarization.

The use of alefacept in the treatment of psoriasis.

Alefacept (AMEVIVE or LFA#TIP, Biogen) is the newest effective systemic therapy for chronic plaque psoriasis and was approved by the US FDA in January 2003. Clinical studies have shown that alefacept, given via weekly IM or IV injections for 12 weeks, was well tolerated, with no reported serious adverse events. Most significantly, it was found that alefacept provides a long-lasting remittive effect. These findings support the use of alefacept as a viable treatment of psoriasis, without the toxicities associated with some of the current systemic treatments available.

99.6% spin-flip efficiency in the presence of a strong Siberian snake.

We recently studied the spin-flipping efficiency of an rf-dipole magnet using a 120-MeV horizontally polarized proton beam stored in the Indiana University Cyclotron Facility Cooler Ring, which contained a nearly full Siberian snake. We flipped the spin by ramping the rf dipole's frequency through an rf-induced depolarizing resonance. By adiabatically turning on the rf dipole, we minimized the beam loss. After optimizing the frequency ramp parameters, we used 100 multiple spin flips to measure a spin-flip efficiency of 99.63+/-0.05%. This result indicates that spin flipping should be possible in very-high-energy polarized storage rings, where Siberian snakes are certainly needed and only dipole rf-flipper magnets are practical.

Transcriptional activity of the promoter region of rat frizzled-related protein gene.

Frizzled-related protein (Frp) is a new family of secreted proteins involved in tumorigenesis and Wnt-signaling pathway. Previous study has shown that rat Frp (rFrp) gene was found to be differentially expressed in Rat 6 fibroblast cell line overexpressing p53(val135) (R6#13-8). The rFrp gene was otherwise silent in normal parental Rat 6 cells. To elucidate the molecular basis of the transcriptional activation of rFrp, we have isolated and analyzed a 2-kilobase pair promoter region of the rFrp gene. Mapping of transcription initiation sites of rFrp showed the existence of multiple initiation sites. Transfection studies of serial deletion constructs in both Rat 6 and CHOK1 cell lines revealed that the region from -202 to -144 contains cis-acting elements essential for the efficient transcription of rFrp. This work provides a transcriptional regulation basis for Frp and gives insight into its implication in tumorigenesis.

Immunogenicity of a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine when mixed with a diphtheria-tetanus-acellular pertussis-hepatitis B combination vaccine.

BACKGROUND: Combination vaccines are urgently needed to reduce the number of injections given to young children. The aim of the study was to evaluate the safety and immunogenicity of a combination vaccine that contains diphtheria and tetanus toxoids and acellular pertussis antigens (DTaP), recombinant hepatitis B surface antigen (HepB) and Haemophilus influenzae type b (Hib) polysaccharide conjugated to tetanus toxoid (PRP-T). METHODS: Four hundred five infants were randomized equally to three groups and immunized at 2, 4 and 6 months of age with: (1) DTaP/HepB vaccine used to reconstitute lyophilized PRP-T vaccine and administered as a single injection; (2) DTaP/HepB vaccine and PRP-T vaccine administered as two separate injections; or (3) DTaP, HepB and PRP-T vaccines administered as three separate injections. Safety was closely monitored, and blood specimens were obtained to assess antibody responses to each vaccine antigen. RESULTS: All study vaccines were well-tolerated, and the rates of systemic and injection site reactions were similar between groups. After the third dose the geometric mean antibody concentrations to Hib were significantly lower in subjects in Group 1 (1.63 microg/ml) compared with subjects in Groups 2 and 3 (6.26 and 6.15 microg/ml, respectively; P < 0.0001). Subjects with antibody concentrations <1.0 microg/ml after the third dose responded well to a booster dose of Hib conjugate vaccine given at 11 to 15 months of age (41 of 44 with anti-PRP > or = 1.0 microg/ml). Differences between groups for antibody responses to the other vaccine components were not clinically significant. CONCLUSIONS: Infants given a combined DTaP/ HepB/PRP-T vaccine experienced a significantly lower antibody response to the PRP-T component than infants given PRP-T vaccine as a separate injection. However, the immune response to a booster dose of Hib conjugate vaccine indicated the presence of immunologic memory.

Influence of DL methionine and sodium metabisulphite on the photostability of vitamin k1.

On exposure to UV light at 254 nm in a borosilicate glass actinometer, vitamin k1 decomposed rapidly with a degradation rate constant of 7.63 day-1. Under UV irradiation, DL methionine and sodium metabisulphite were found to have some photostabilizing effect for vitamin k1 formulations. The degradation rates were reduced by 43.4% and 60.4% in the presence of 0.1% w/v of DL methionine and 0.2% w/v of sodium metabisuphite, respectively. When vitamin k1 formulations were stored at room temperature in clear glass bottles and exposed to the weaker light source of both room fluorescent light and natural daylight, vitamin k1 decomposed at a much slower degradation rate constant of 0.31 day-1. Despite the slower degradation rate, DL methionine and sodium metabisuphite failed to protect vitamin k1 from degradation on exposure to this weaker light source. When vitamin k1 was stored in white plastic bottles under the same testing conditions, the photo-protective effect of these photostabilizers reappeared. The protection provided extended the shelf-life from one day to 2.5 days. When amber glass bottles replaced white plastic bottles as storage containers, vitamin k1 was found stable on an open bench for at least 30 days. Such stability was also observed when vitamin k1 was stored in a refrigerator in either white plastic bottles or amber bottles. Findings in this study showed that package and storage conditions that shield the products from light are still the most efficient ways to maintain the photostability of vitamin k1. However, photostabilizers such as DL methionine and sodium metabisulphite may provide additional protection to vitamin k1 when it is stored in less effective light-resistant containers.

Bilateral Candida parapsilosis endophthalmitis.

We describe a patient with bilateral, delayed endophthalmitis who underwent bilateral pars plana vitrectomy, total capsulectomy, intraocular lens exchange, intravitreal injection of amphotericin B, and oral fluconazole therapy. The long-term inflammation resolved, and vitreous cultures from both eyes yielded Candida parapsilosis. Histopathologic examination revealed sequestered yeast forms in the capsular bags.

Retinal venous occlusive disease.

Occlusions of the retinal venous system are the second most common retinal vascular disease after diabetic retinopathy. Patients present with sudden vision loss or may be asymptomatic. Retinal vein occlusions are classified into branch or central occlusions. Laser photocoagulation and vitreoretinal surgical techniques are used to treat the complications of macular edema, neovascularization, vitreous hemorrhage and retinal detachment.