Is autophagy induction by PARP inhibitors a target for therapeutic benefit?

PARP inhibitors have proven to be effective in conjunction with conventional therapeutics in the treatment of various solid as well as hematologic malignancies, particularly when the tumors are deficient in DNA repair pathways. However, as the case with other chemotherapeutic agents, their effectiveness is often compromised by the development of resistance. PARP inhibitors have consistently been reported to promote autophagy, a process that maintains cellular homeostasis and acts as an energy source by the degradation and reutilization of damaged subcellular organelles and proteins. Autophagy can exhibit different functional properties, the most prominent being cytoprotective. In addition, both cytotoxic and non-protective functions forms have also been identified. In this review, we explore the available literature regarding the different roles of autophagy in response to clinically-used PARP inhibitors, highlighting the possibility of targeting autophagy as an adjuvant therapy to potentially increase the effectiveness of PARP inhibition and to overcome the development of resistance.     

Review article: Perioperative care of patients with epidermolysis bullosa: proceedings of the 5th international symposium on epidermolysis bullosa,Santiago Chile,December 4–6, 2008

Epidermolysis bullosa (EB) has become recognized as a multisystem disorder that poses a number of pre‐, intra‐, and postoperative challenges. While anesthesiologists have long appreciated the potential difficult intubation in patients with EB, other systems can be affected by this disorder. Hematologic, cardiac, skeletal, gastrointestinal, nutritional, and metabolic deficiencies are foci of preoperative medical care, in addition to the airway concerns. Therefore, multidisciplinary planning for operative care is imperative. A multinational, interdisciplinary panel of experts assembled in Santiagio, Chile to review the best practices for perioperative care of patients with EB. This paper presents guidelines that represent a synthesis of evidence‐based approaches and the expert consensus of this panel and are intended to aid physicians new to caring for patients with EB when operative management is indicated. With proper medical optimization and attention to detail in the operating room, patients with EB can have an uneventful perioperative course.     

Tumor-initiating cells of various tumor types exhibit differential angiogenic properties and react differently to antiangiogenic drugs

Tumor-initiating cells (TICs) are a subtype of tumor cells believed to be critical for initiating tumorigenesis. We sought to determine the angiogenic properties of TICs in different tumor types including U-87MG (glioblastoma), HT29 (colon), MCF7 (breast), A549 (non-small-cell lung), and PANC1 (pancreatic) cancers. Long-term cultures grown either as monolayers ("TIC-low") or as nonadherent tumor spheres ("TIC-high") were generated. The TIC-high fractions exhibited increased expression of stem cell surface markers, high aldehyde dehydrogenase activity, high expression of p21, and resistance to standard chemotherapy in comparison to TIC-low fractions. Furthermore, TICs from U-87MG and HT29 but not from MCF7, A549, and PANC1 tumor types possess increased angiogenic activity. Consequently, the efficacy of vascular endothelial growth factor-A (VEGF-A) neutralizing antibody is limited only to those tumors that are dependent on VEGF-A activity. In addition, such therapy had little or reversed antiangiogenic effects on tumors that do not necessarily rely on VEGF-dependent angiogenesis. Differential angiogenic activity and antiangiogenic therapy sensitivity were also observed in TICs of the same tumor type, suggesting redundant angiogenic pathways. Collectively, our results suggest that the efficacy of antiangiogenic drugs is dependent on the angiogenic properties of TICs and, therefore, can serve as a possible biomarker to predict antiangiogenic treatment efficacy. Stem Cells2012;30:1831-1841.     

Transmission of Vertical Vibration to the Human Foot and Ankle

The load absorbing capability of the foot and ankle system (FAS) was characterized by measuring the transmissibility and the phase delay at the medial malleolus and the tibial tuberosity. The FAS of twenty subjects were exposed to sinusoidal vertical excitation (10–50 Hz with 5 Hz increments and peak to peak acceleration of 17.9 m/s²) while sitting as a function of the external mass (0, 2.3, and 4.5 kg) and the foot postures (midstance, plantarflexion, and dorsiflexion). The results showed that the FAS plays important role in vibration transmission of lower leg. Adding extra mass affected a resonant frequency at the medial malleolus: 15–25, 30–35, and 35 Hz for with no additional mass, 2.3, and 4.5 kg, respectively. However, the changed postures of the FAS did not show significant effect on the resonant frequency. The applied mass affected the stiffness increase of the FAS and consequently resulted in the increase of the resonant frequency. This result supports the assertion that the resonant frequency of overweight or obese persons is similar to the major frequency component (25–35 Hz) of the heel strike.     

Surgical treatment of chronic post-traumatic osteomyelitis of the femur in pseudarthrosis, ununited fractures and defects]

The authors have analyzed the results of treatment for chronic posttraumatic osteomyelitis of the femoral bone in 69 cases of ununited fractures, false joints ad femoral bone defects. The treatment included surgical sanation of the osteomyelitic nidus together with aspiration lavage drainage and extranidal osteosynthesis by external fixation as well as local and general antibacterial therapy. In 13 cases free bone autoplasty of the osteomyelitic cavities or defects was used together with spongious structures of iliac bone (crest and wing), in 2 of these patients it was applied for replacement of the large defects of the diaphysis of the femoral bone (8 and 12 cm). In 57 patients surgical treatment was carried out in one stage, a major requisite for this was the opportunity for joining bone fragments inside the open wound after sequestrectomy as well as stable external fixation by the apparatus. This treatment gave successful results in 97% of patients.     

Four-dimensional ultrasound guidance during epidural anaesthesia

Background

Four-dimensional (4D) ultrasound scanning (3D real-time mode) can improve the orientation of the anatomy of the area of interest and navigation by controlling the needle position. The objectives of this study were to identify the optimal technique for navigation and to assess clinically the efficacy of 4D ultrasound navigation for epidural anaesthesia at lower thoracic and lumbar levels.

Design

Single-centre case series study was performed.

Methods

Sixteen patients were included. First, conventional 2D scanning was performed, followed by 4D reconstruction, and the basic tissues with high acoustic impedance (bone structures) and available acoustic windows were determined. Movement of the needle was controlled on the sagittal plane in 2D mode and at the same time in 4D mode (3D real-time mode). To improve the visibility of the needle, the 3D reconstruction was rotated during manipulation.

Results

The 4D scanning mode provided 100 % visibility of compact bone tissues and 93 % visibility of the posterior complex. Needle visualisation strongly depended on the rotation of the reconstructed image with the sensor remaining motionless. The needle was redirected in one patient (7 %) because it was in contact with the vertebral lamina. Dilation of the epidural space during saline injection was observed in five patients (36 %). A change in the puncture level was not required any patients; no complications associated with epidural puncture were observed.

Conclusions

Ultrasound navigation in 4D could improve epidural anaesthesia due to the enhanced spatial orientation of the operator. The technique of “position contrast” should be used for reliable needle visualisation.

Electronic supplementary material

The online version of this article (doi:10.1007/s40477-014-0150-1) contains supplementary material, which is available to authorized users.     

Amplification of Sca-1+ Lin- WGA+ cells in serum-free cultures containing steel factor, interleukin-6, and erythropoietin with maintenance of cells with long-term in vivo reconstituting potential

Normal murine bone marrow (BM) cells were sorted on the basis of low forward and orthogonal light scatter properties, Sca-1 expression (Sca- 1+), lack of staining with a cocktail of mature hematopoietic lineage markers (Lin-), and binding of wheat germ agglutinin (WGA+). This approach allowed the reproducible isolation of a very small subpopulation (0.037% +/- 0.023% of all nucleated BM cells) that was approximately 400-fold enriched in cells capable of reconstituting both lymphoid and myeloid lineages in lethally irradiated recipients. Transplantation of 30 or 10 of these Sca-1+Lin-WGA+ cells resulted in > or = to 20% donor-derived nucleated peripheral blood cells 3 months posttransplantation in 100% and 22% of the recipients, respectively. When Sca-1+Lin-WGA+ cells were cultured in serum-free medium supplemented with Steel factor, interleukin-6 (IL-6), and erythropoietin (with or without IL-3), a large increase in total cell number, including cells with an Sca-1+Lin-WGA+ phenotype was observed. Single cell cultures showed that 90% to 95% of the input cells underwent at least one division during the first 2 weeks and the remainder died. Interestingly, this proliferative response was not accompanied by a parallel increase in the number of cells with both lymphoid and myeloid repopulating potential in vivo, as quantitation of these by limiting dilution analysis showed they had decreased slightly (1.3-fold) but not significantly below the number initially present. These results demonstrate that Sca-1+Lin-WGA+ cells with long-term repopulating potential can be maintained for 2 weeks in a serum- and stroma cell-free culture, providing a simple in vitro system to study their behavior under well-defined conditions. The observed expansion of Sca-1+Lin-WGA+ cells in vitro without a concomitant increase in reconstituting cells also shows that extensive functional heterogeneity exists within populations of cells with this surface phenotype.     

Prevention of overuse injuries of the foot by improved shoe shock attenuation. A randomized prospective study.

In a randomized prospective study among 390 recruits, the hypothesis that improved shoe shock attenuation could lessen the incidence of overuse injuries was tested. During the 14 weeks of training, 90% of the recruits sustained overuse injuries. Recruits training in a modified basketball shoe had a statistically significant lower incidence of metatarsal stress fractures and foot overuse injuries, compared with standard infantry boots, but their overall incidence of overuse injuries was not reduced. The effect of improved shoe shock attenuation was limited to those overuse injuries resulting from vertical impact loads.