SummaryMany tumors are hierarchically organized with a minority cell population that has stem-like properties and enhanced ability to initiate tumorigenesis and drive therapeutic relapse. These cancer stem cells (CSCs) are typically identified by complex combinations of cell-surface markers that differ among tumor types. Here, we developed a flexible lentiviral-based reporter system that allows direct visualization of CSCs based on functional properties. The reporter responds to the core stem cell transcription factors OCT4 and SOX2, with further selectivity and kinetic resolution coming from use of a proteasome-targeting degron. Cancer cells marked by this reporter have the expected properties of self-renewal, generation of heterogeneous offspring, high tumor- and metastasis-initiating activity, and resistance to chemotherapeutics. With this approach, the spatial distribution of CSCs can be assessed in settings that retain microenvironmental and structural cues, and CSC plasticity and response to therapeutics can be monitored in real time.
Painful terminal neuromas resulting from nerve injury following amputation are common. However, there is currently no universally accepted gold standard of treatment for this condition. A comprehensive literature review is presented on the treatment of terminal neuromas. Four categories of terminal neuroma surgical procedures are assessed: epineurial closure; nerve transposition with implantation; neurorrhaphy, and alternate target reinnervation. Significant patient and case studies are highlighted in each section, focusing on surgical technique and patient outcome metrics. Studies presented consisted of a PubMed search for "terminal neuromas," without year limitation. The current available research supports the use of implantation into muscle for the surgical treatment of terminal neuromas. However, this technique has several fundamental flaws that limit its utility, as it does not address the underlying physiology behind neuroma formation. Regenerative peripheral nerve interfaces and targeted muscle reinnervation are 2 techniques that seem to offer the most promise in preventing and treating terminal neuroma formation. Both techniques are also capable of generating control signals which can be used for both motor and sensory prosthetic control. Such technology has the potential to lead to the future restoration of lost limb function in amputees. Further clinical research employing larger patient groups with high-quality control groups and reproducible outcome measures is needed to determine the most effective and beneficial surgical treatment for terminal neuromas. Primary focus should be placed on investigating techniques that most closely approximate the theoretically ideal neuroma treatment, including targeted muscle reinnervation and regenerative peripheral nerve interfaces.
Each year, approximately 185,000 Americans suffer the devastating loss of a limb. The effects of upper limb amputations are profound because a person's hands are tools for everyday functioning, expressive communication, and other uniquely human attributes. Despite the advancements in prosthetic technology, current upper limb prostheses are still limited in terms of complex motor control and sensory feedback. Sensory feedback is critical to restoring full functionality to amputated patients because it would relieve the cognitive burden of relying solely on visual input to monitor motor commands and provide tremendous psychological benefits. This article reviews the latest innovations in sensory feedback and argues in favor of peripheral nerve interfaces. First, the authors examine the structure of the peripheral nerve and its importance in the development of a sensory interface. Second, the authors discuss advancements in targeted muscle reinnervation and direct neural stimulation by means of intraneural electrodes. The authors then explore the future of prosthetic sensory feedback using innovative technologies for neural signaling, specifically, the sensory regenerative peripheral nerve interface and optogenetics. These breakthroughs pave the way for the development of a prosthetic limb with the ability to feel.
Changes in standard-of-care for breast augmentation are reflected by the evolving practice patterns of plastic surgeons. This is best evidenced by the dramatic increase in use of antibiotic and DVT prophylaxis from 2011 to 2015.
Many tumors consist of a hierarchy of cells with different proliferative and developmental potential. A small number of cancer stem cells (CSCs) give rise to a larger population of highly proliferative, committed progenitor cells, which may then undergo limited differentiation. Importantly, CSCs are uniquely capable of initiating and sustaining tumorigenesis, and they have been implicated in driving disease recurrence after cancer therapy. Thus understanding CSC biology will be critical to the development of more effective therapies. CSCs are most commonly identified by FACS analysis but the optimal marker combinations are very dependent on the tissue and specific cell-of-origin of the tumor, and they cannot be used to monitor the CSCs in situ, with all the microenvironmental cues intact. Such markers cannot readily be used for real-time assessment of stem cell behavior at a single cell rather than a population level. To address this problem, we have developed and validated a novel lentiviral-based reporter system for direct visualization, quantitation and isolation of the cells with CSC properties. The construct consists of a tandemly repeated composite Sox2-Oct4 response element (SORE6) driving expression of a destabilized green fluorescent protein reporter. The reporter responds to the presence of the core stem cell transcription factors Oct4 and Sox2, with further stem cell selectivity and kinetic resolution coming from the use of a proteosome-targeting degron on the fluorescent protein. Using the human MCF10CA1h breast cancer cell line, we have shown that SORE6-GFP+ cells within the cell population are undifferentiated and enriched for stem cell markers. These cells can self-renew and regenerate GFP- cells, show enhanced asymmetric division, and are enriched for tumorsphere formation in vitro. Most importantly the SORE6-GFP+ cells are enriched for tumor-initiating and metastasis-initiating ability in vivo and they are relatively resistant to chemotherapeutics both in vitro and in vivo. Thus by a number of criteria, the reporter is marking a cell population that is substantially enriched for CSCs. The reporter works in primary human breast cancer cultures and patient-derived xenografts in addition to established cell line models. Our novel imaging approach opens up the possibility of assessing the spatial distribution of CSCs and temporal changes in CSC properties in experimental settings that retain the complex microenvironmental and structural cues of the tumor bed. Citation Format: Binwu Tang, Asaf Raviv, Dominic Esposito, Catherine Daniel, Bao Tram Nghiem, Susan Garfield, Langston Lim, Poonam Mannan, Ana Robles, William Smith, Joshua Zimmerberg, Rea Ravin, Lalage Wakefield. A novel reporter system with potential for in situ assessment of tumor microenvironmental effects on cancer stem cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B45. doi:10.1158/1538-7445.CHTME14-B45
Background Breast conservation therapy is defined as partial mastectomy with subsequent radiation therapy and is the treatment for early-stage breast cancer. However, the unwanted risks of radiation must be considered as well as the impact on future breast reconstruction options. The purpose of this study was to assess the preference of plastic surgeons when given the hypothetical diagnosis of breast cancer. Methods A survey assessing treatment preference of 3 hypothetical breast cancer diagnosis scenarios was designed and distributed by American Society of Plastic Surgeons via e-mail invite to its members. Results The risk of cancer recurrence was the most common reason for treatment preferences of all three choices. However, for ductal carcinoma in situ, unilateral mastectomy with implant-based reconstruction is the preferred option with the second most influential reason of avoiding the risks of radiation therapy. For invasive ductal carcinoma node negative, unilateral mastectomy with implant-based reconstruction was the preferred option also due to risks of radiation therapy and anxiety of future surveillance. For invasive ductal carcinoma node positive, bilateral mastectomy with implant-based reconstruction was the preferred choice because of anxiety of future surveillance and also risks of radiation therapy. Conclusions In general, plastic surgeons did not prefer breast conservation therapy for in situ and early-stage breast cancer. Although the most common rationale for total mastectomy was risk of cancer recurrence for all disease severity, risks of radiation therapy are real and play an integral role in the decision-making process. In understanding our own biases, we can help better empathize with patients in consultation for breast reconstruction.
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