Static strengthening and fatigue blunt-notch sensitivity in low-carbon steels

The influence of four different static strengthenings on the fatigue blunt-notch sensitivity of a low-carbon steel with a ferrite–pearlite microstructure was analyzed and modeled. The analysis was made using a model previously derived which estimates the fatigue limit of blunt notched components by means of the parameter ktd defined as the stress concentration introduced by the notch at a distance d from the notch root surface equal to the distance between microstructural barriers. While the distance d between microstructural barriers is kept constant by keeping constant the grain size, the effective resistance of the microstructural barriers to crack propagation is increased by static strengthening. The analyses have shown the influence of the distribution and effective resistance of the first two or three microstructural barriers on fatigue blunt-notch sensitivity.Fil: Chapetti, Mirco Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; ArgentinaFil: Katsura, N.. Nagoya University. Material Science and Engineering; JapónFil: Tagawa, T.. Nagoya University. Material Science and Engineering; JapónFil: Miyata, T.. Nagoya University. Material Science and Engineering; Japó

Primary Squamous Cell Carcinoma of the Urinary Bladder Presenting as Peritoneal Carcinomatosis

We report an unusual case of a 78-year-old Caucasian female, who presented with peritoneal carcinomatosis and hypercalcemia, and was found to have a rapidly progressive primary squamous cell carcinoma of the urinary bladder. Squamous cell bladder carcinoma is a rare malignancy in the United States, accounting for just 1–3% of bladder tumors. Interestingly our patient lacked the established risk factors, including exposure to the parasite Schistosoma haematobium, recurrent urinary tract infections, bladder calculi, radiation exposure, chronic indwelling catheter, neurogenic bladder, or tobacco abuse. Although hypercalcemia has been rarely described, an initial presentation of peritioneal carcinomatosis has not been previously reported

The Current Role of Androgen Deprivation in Patients Undergoing Dose-Escalated External Beam Radiation Therapy for Clinically Localized Prostate Cancer

Purpose. To review existing literature on the role of androgen deprivation therapy (ADT) with dose escalated radiation therapy. Methods and Materials. A PubMed search was undertaken to identify relevant articles. Results. Multiple recent studies were identified examining the role of ADT in the current era of radiation dose-escalation. Among the reviewed studies, varying radiation doses and techniques, ADT regimens, and patient selection criteria were utilized. Conflicting results were reported, with some studies demonstrating a benefit of delivering a higher radiation dose with ADT. Other studies failed to show significant benefits with the addition of ADT to dose-escalated RT. Conclusions. The benefit of adding ADT to dose-escalated RT is still uncertain. Prospective randomized trials, several of which are ongoing, are necessary to more adequately examine this issue. In the interim, physicians and patients should continue to utilize the existing data to weigh the risks and benefits of each approach to therapy

Ku70 alleviates neurodegeneration in drosophila models of Huntington's disease

DNA damage accumulates in genome DNA during the long life of neurons, thus DNA damage repair is indispensable to keep normal functions of neurons. We previously reported that Ku70, a critical molecule for DNA double strand break (DSB) repair, is involved in the pathology of Huntington's disease (HD). Mutant huntingtin (Htt) impaired Ku70 function via direct interaction, and Ku70 supplementation recovered phenotypes of a mouse HD model. In this study, we generate multiple Drosophila HD models that express mutant huntingtin (Htt) in eye or motor neuron by different drivers and show various phenotypes. In such fly models, Ku70 co-expression recovers lifespan, locomotive activity and eye degeneration. In contrast, Ku70 reduction by heterozygous null mutation or siRNA-mediated knock down accelerates lifespan shortening and locomotion disability. These results collectively support that Ku70 is a critical mediator of the HD pathology and a candidate therapeutic target in HD

Prostate-Specific Membrane Antigen-Based Therapeutics

Prostate cancer (PC) is the most common noncutaneous malignancy affecting men in the US, leading to significant morbidity and mortality. While significant therapeutic advances have been made, available systemic therapeutic options are lacking. Prostate-specific membrane antigen (PSMA) is a highly-restricted prostate cell-surface antigen that may be targeted. While initial anti-PSMA monoclonal antibodies were suboptimal, the development of monoclonal antibodies such as J591 which are highly specific for the external domain of PSMA has allowed targeting of viable, intact prostate cancer cells. Radiolabeled J591 has demonstrated accurate and selective tumor targeting, safety, and efficacy. Ongoing studies using anti-PSMA radioimmunotherapy with 177Lu-J591 seek to improve the therapeutic profile, select optimal candidates with biomarkers, combine with chemotherapy, and prevent or delay the onset of metastatic disease for men with biochemical relapse. Anti-PSMA monoclonal antibody-drug conjugates have also been developed with completed and ongoing early-phase clinical trials. As PSMA is a selective antigen that is highly overexpressed in prostate cancer, anti-PSMA-based immunotherapy has also been studied and utilized in clinical trials

Gelatine Cavity Dynamics of High-Speed Sphere Impact

We investigate the impact and penetration of a solid sphere passing through gelatine at various impact speeds up to 143.2 m s-1 Tests were performed with several concentrations of gelatine. Impacts for low elastic Froude number Fre a ratio between inertia and gelatine elasticity, resulted in rebound. Higher Fre values resulted in penetration, forming cavities with prominent surface textures. The overall shape of the cavities resembles those observed in water-entry experiments, yet they appear in a different order with respect to increasing inertia: rebound, quasi-seal, deep-seal, shallow-seal and surface-seal. Remarkably, similar to the We – Bo phase diagram in water-entry experiments, the elastic Froude number Fre and elastic Grashof number Gre (a ratio between gravity and gelatine elasticity) classify all five different phenomena into distinguishable regimes. We find that Fre can be a good indicator to describe the cavity length H , particularly in the shallow-seal regime. Finally, the evolution of cavity shape, pinch-off depth, and lower cavity radius are investigated for different Fre values

Review of Salvage Therapy for Biochemically Recurrent Prostate Cancer: The Role of Imaging and Rationale for Systemic Salvage Targeted Anti-Prostate-Specific Membrane Antigen Radioimmunotherapy

Despite local therapy with curative intent, approximately 30% of men suffer from biochemical relapse. Though some of these PSA relapses are not life threatening, many men eventually progress to metastatic disease and die of prostate cancer. Local therapy is an option for some men, but many have progression of disease following local salvage attempts. One significant issue in this setting is the lack of reliable imaging biomarkers to guide the use of local salvage therapy, as the likely reason for a low cure rate is the presence of undetected micrometastatic disease outside of the prostate/prostate bed. Androgen deprivation therapy is a cornerstone of therapy in the salvage setting. While subsets may benefit in terms of delay in time to metastatic disease and/or death, research is ongoing to improve salvage systemic therapy. Prostate-specific membrane antigen (PSMA) is highly overexpressed by the majority of prostate cancers. While initial methods of exploiting PSMA's high and selective expression were suboptimal, additional work in both imaging and therapeutics is progressing. Salvage therapy and imaging modalities in this setting are briefly reviewed, and the rationale for PSMA-based systemic salvage radioimmunotherapy is described

Synthetic DNA immunotherapy in biochemically relapsed prostate cancer

Background: INO-5150 (PSA and PSMA) +/- INO-9012 (IL-12), a synthetic DNA immunotherapy, was assessed for safety, immunogenicity and efficacy in biochemically recurrent prostate cancer patients (pts). Methods: Phase I, open-label, multi-center study in the US included pts with rising PSA after surgery and/or RT, PSA doubling time (PSADT) \u3e3 months (mos), testosterone \u3e150 ng/dL and no concurrent ADT. Safety, immunogenicity and efficacy (PSA kinetics, PFS) were evaluated in 4 treatment arms of 15 pts each. Arms A: 2mg INO-5150, B: 8.5 mg INO-5150, C: 2mg INO-5150 + 1mg INO-9012 and D: 8.5mg INO-5150 + 1mg INO-9012. Pts received 4 IM doses of vaccine followed by electroporation on day 0, wks 3, 12 and 24 and were followed for 72 wks. Results: 50/61 (82%) pts completed all visits and treatments were well tolerated with no safety concerns. Median PFS for overall population [N = 61, baseline (D0) PSADT range (mos) 1.5-217.1, median 9.8] and for a subset of pts with D0 PSADT ≤12mos (N = 36) has not yet been reached (FU 3-19 mos). 86% of pts with D0 PSADT ≤12 mos were progression free through 19mos FU. 27 out of 36 (75%) pts with D0 PSADT≤ 12 mos had disease stabilization at wks 27 evidenced by significant improvement in log2PSA change over time (slope) and PSADT from D0 (Slope=0.19 declined to 0.1, PSADT=5.3 improved to 10.1 mos, p = \u3c0.0001). This effect was maintained at wk 72 (Slope=0.09, PSADT=10.6, p = \u3c0.0001). Immunogenicity was observed in 77% (47/61) of pts by multiple immunologic assessments. Patient immunogenicity to INO-5150 as determined by CD38 and Perforin + CD8 T cell immune reactivity correlated with attenuated % PSA rise compared to pts without reactivity (p = 0.05, n = 50). Conclusions: INO-5150 +/- INO-9012 was safe, well tolerated and immunogenic. Clinical efficacy was observed in the patients with D0 PSADT≤ 12 mos as evidenced by a significant dampening of log2PSA change over time and increased PSADT up to 72 weeks FU. Additional genomic analyses are ongoing to further elucidate the correlation of immunologic efficacy and clinical benefit. (NCT02514213)