High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults.

Since the early 1980s high dose chemotherapy with autologous hematopoietic stem cell support was adopted by many oncologists as a potentially curative option for solid tumors, supported by a strong rationale from laboratory studies and apparently convincing results of early phase II studies. As a result, the number and size of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) to prove or disprove its value was largely insufficient. In fact, with the possible exception of breast carcinoma, the benefit of a greater escalation of dose of chemotherapy with stem cell support in solid tumors is still unsettled and many oncologists believe that this approach should cease. In this article, we critically review and comment on the data from studies of high dose chemotherapy so far reported in adult patients with small cell lung cancer, ovarian cancer, germ cell tumors and sarcomas.

Potential and limitations of regulatory T-cell therapy in solid organ transplantation.

Over the past few years, the therapeutic potential of Treg has been highlighted in the field of autoimmune diseases and after allogeneic transplantation. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non-manipulated individuals, in particular when facing strong immune activation and expanding effector cells, such as in response to an allograft. Here we review current approaches being explored for Treg expansion in the perspective of clinical therapeutic protocols. We describe different Treg subsets that could be suitable for clinical application, as well as discuss factors such as the required dose of Treg, their antigen-specificity and in vivo stability, that have to be considered for optimal Treg-based immunotherapy in transplantation. Since Treg may not be sufficient as stand-alone therapy for solid organ transplantation in humans, we draw attention to possible hurdles and combination therapy with immunomodulatory drugs that could possibly improve the in vivo efficacy of Treg.

Audit report on the Wayne-Ringgold-Decatur County Solid Waste Management Commission for the year ended June 30, 2013

Audit report on the Wayne-Ringgold-Decatur County Solid Waste Management Commission for the year ended June 30, 2013

Audit report on the Pocahontas County Solid Waste Commission for the year ended June 30, 2013

Audit report on the Pocahontas County Solid Waste Commission for the year ended June 30, 2013

Audit report on the Butler County Solid Waste Commission for the year ended June 30, 2013

Audit report on the Butler County Solid Waste Commission for the year ended June 30, 2013

Pharmacokinetic and pharmacodynamic evaluation of valganciclovir in solid organ transplant patients

Goal: To validate oral vatgancictovir (VGC) in the prophylaxis of CMV infection in Lung (Lu) and Liver (L) recipients and in the treatment of CMV infection/disease in solid organ transplant recipients, using pharmacokinetic and pharmacodynamic studies in comparison with i/v gancicLovir (GCV). Methods: patients undergoing organ transpLantation donor or recipient CMV-seropositive receiving VGC prophylaxis for a period of 3 months (D+/R- Lung recipients, 6 months) were enroLLed. Heart (H), Lu, and L recipients received 900mg VGC q.d., adjusted to kidney (K) function. No K recipients received more than 450mg of VGC q.d. GCV trough (Ctrough) and peak (Cpeak = 3 hours after drug administration) LeveLs, and CMV DNA were measured at 7, 30, and 60 days post-transpLant (prophyLactic study). Patients who developed CMV infection/disease after stopping prophylaxis were treated with VGC (1800mg per day adjusted to K function and GCV blood LeveLs). GCV trough and peak LeveLs, and CMV DNA were measured weekly for the first 3 weeks and biweekly thereafter, until therapy cessation (therapeutic study). PLasma concentration of GCV is measured by HPLC. Results: In the first 8 prophyLaxed patients (6 K, and 1 L and 1 H transplant recipient) of 450mg VGC q.d., the average GCV concentration was 0.5±0.3 mg/t at trough, and 3.9±l.0mg/t 3 hours after administration. Inter-patient variability was substantiaL, especiaLLy for Ctrough (63% of total variance), which correlated with the patient's estimated gtomerutar filtration rate (r square = 42%). No CMV DNA was detected during VGC prophy- Laxis. Two patients (1 H and 1 L) were treated for Late CMV disease. Average GCV Cpeak were 8.9±2.3 mg/L and 4.6±0.5 rag/L, and GCV Ctrough were 2.0±0.9 mg/t and 1.6±0.2 mg/t respectively in each patient during induction phase. VGC treatment afforded a decrease in CMV DNA from 5.2 and 4.4 Log copies/10E6 cettutes at week 0, to 3.9 and 3.0 at week 1, and 3.3 and 2.1 at week 3, respectively.

Synthesis of triheptanoin and formulation as a solid diet for rodents

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 3040% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.

The estrogen-responsive element as an inducible enhancer: DNA sequence requirements and conversion to a glucocorticoid-responsive element.

The estrogen-responsive element (ERE) present in the 5'-flanking region of the Xenopus laevis vitellogenin (vit) gene B1 has been characterized by transient expression analysis of chimeric vit-tk-CAT (chloramphenicol acetyltransferase) gene constructs transfected into the human estrogen-responsive MCF-7 cell line. The vit B1 ERE behaves like an inducible enhancer, since it is able to confer estrogen inducibility to the heterologous HSV thymidine kinase (tk) promoter in a relative position- and orientation-independent manner. In this assay, the minimal B1 ERE is 33 bp long and consists of two 13 bp imperfect palindromic elements both of which are required for the enhancer activity. A third imperfect palindromic element is present further upstream within the 5'-flanking region of the gene but is unable to confer hormone responsiveness by itself. Similarly, neither element forming the B1 ERE can alone confer estrogen inducibility to the tk promoter. However, in combinations of two, all three imperfect palindromes can act cooperatively to form a functional ERE. In contrast a single 13 bp perfect palindromic element, GGTCACTGTGACC, such as the one found upstream of the vit gene A2, is itself sufficient to act as a fully active ERE. Single point mutations within this element abolish estrogen inducibility, while a defined combination of two mutations converts this ERE into a glucocorticoid-responsive element.

T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy.

Cancer immunotherapy has great promise, but is limited by diverse mechanisms used by tumors to prevent sustained antitumor immune responses. Tumors disrupt antigen presentation, T/NK-cell activation, and T/NK-cell homing through soluble and cell-surface mediators, the vasculature, and immunosuppressive cells such as myeloid-derived suppressor cells and regulatory T cells. However, many molecular mechanisms preventing the efficacy of antitumor immunity have been identified and can be disrupted by combination immunotherapy. Here, we examine immunosuppressive mechanisms exploited by tumors and provide insights into the therapies under development to overcome them, focusing on lymphocyte traffic.

Importance of polyethylene thickness in total shoulder arthroplasty: a finite element analysis.

BACKGROUND: Articular surfaces reconstruction is essential in total shoulder arthroplasty. Because of the limited glenoid bone support, thin glenoid component could improve anatomical reconstruction, but adverse mechanical effects might appear. METHODS: With a numerical musculoskeletal shoulder model, we analysed and compared three values of thickness of a typical all-polyethylene glenoid component: 2, 4 (reference) and 6mm. A loaded movement of abduction in the scapular plane was simulated. We evaluated the humeral head translation, the muscle moment arms, the joint force, the articular contact pattern, and the polyethylene and cement stress. Findings Decreasing polyethylene thickness from 6 to 2mm slightly increased humeral head translation and muscle moment arms. This induced a small decreased of the joint reaction force, but important increase of stress within the polyethylene and the cement mantel. Interpretation The reference thickness of 4mm seems a good compromise to avoid stress concentration and joint stuffing.

Nonlinear Finite Element Study of Piles in Integral Abutment Bridges, HR-227, Part 2, 1982

The highway departments of the states which use integral abutments in bridge design were contacted in order to study the extent of integral abutment use in skewed bridges and to survey the different guidelines used for analysis and design of integral abutments in skewed bridges. The variation in design assumptions and pile orientations among the various states in their approach to the use of integral abutments on skewed bridges is discussed. The problems associated with the treatment of the approach slab, backfill, and pile cap, and the reason for using different pile orientations are summarized in the report. An algorithm based on a state-of-the-art nonlinear finite element procedure previously developed by the authors was modified and used to study the influence of different factors on behavior of piles in integral abutment bridges. An idealized integral abutment was introduced by assuming that the pile is rigidly cast into the pile cap and that the approach slab offers no resistance to lateral thermal expansion. Passive soil and shear resistance of the cap are neglected in design. A 40-foot H pile (HP 10 X 42) in six typical Iowa soils was analyzed for fully restrained pile head and pinned pile head. According to numerical results, the maximum safe length for fully restrained pile head is one-half the maximum safe length for pinned pile head. If the pile head is partially restrained, the maximum safe length will lie between the two limits. The numerical results from an investigation of the effect of predrilled oversized holes indicate that if the length of the predrilled oversized hole is at least 4 feet below the ground, the vertical load-carrying capacity of the H pile is only reduced by 10 percent for 4 inches of lateral displacement in very stiff clay. With no predrilled oversized hole, the pile failed before the 4-inch lateral displacement was reached. Thus, the maximum safe lengths for integral abutment bridges may be increased by predrilling. Four different typical Iowa layered soils were selected and used in this investigation. In certain situations, compacted soil (> 50 blow count in standard penetration tests) is used as fill on top of natural soil. The numerical results showed that the critical conditions will depend on the length of the compacted soil. If the length of the compacted soil exceeds 4 feet, the failure mechanism for the pile is similar to one in a layer of very stiff clay. That is, the vertical load-carrying capacity of the H pile will be greatly reduced as the specified lateral displacement increases.

Audit report on the Delaware County Solid Waste Disposal Commission for the year ended June 30, 2013

Audit report on the Delaware County Solid Waste Disposal Commission for the year ended June 30, 2013

Audit report on the North Central Iowa Regional Solid Waste Agency for the year ended June 30, 2013

Audit report on the North Central Iowa Regional Solid Waste Agency for the year ended June 30, 2013