Articular cartilage defects in the knee are common and possess limited ability to inherently heal. Many of the surgical management options for cartilage repair that result in a hyaline or ...hyaline-like chondral surface have donor site morbidity, are resource intensive, are costly, and may require multiple surgeries. Autologous minced cartilage implantation is an encouraging, single-stage technique that can be safely and efficiently performed arthroscopically to address focal chondral defects in the knee. The limited morbidity and cost-effective nature of using autograft tissue has clear advantages, including an ability to treat patients at the time a clinically relevant defect is identified, increased availability of tissue, reduced patient morbidity with the use of an arthroscopic harvest technique, and the production of a hyaline cartilage repair product with active chondrocytes. Clinically, it has been demonstrated to be superior to microfracture. However, mincing technique may compromise cell viability. A recent porcine model investigation demonstrated that arthroscopic cartilage harvest using a shaver, contains a significantly lower median number of viable chondrocytes compared to open scalpel harvest, resulting in reduced proteoglycans, glycosaminoglycans, aggrecan, and COL2A1 expression, a result of fewer viable chondrocytes. The authors suggest that traditional open scalpel harvest results in a superior single-stage autologous minced cartilage transplantation product with more hyaline-like tissue compared to arthroscopic mincing techniques. However, the findings of the study regarding cell viability after arthroscopic harvest are in stark contrast to previous findings, including our prior work. Pending future research, it is our view that an arthroscopic single-stage autologous cartilage transplant is more reproducible, efficient, and of lower morbidity than open harvest, and we and others have shown the arthroscopic technique to be both safe and effective.
A nuchal-type fibroma (NTF) is a rare, benign, subcutaneous nodule that most frequently occurs in the posterior neck along the midline. It is characterized histologically by bundles of thick collagen ...fibers confined to the dermis and subcutaneous tissue of the posterior neck. Few trauma-related NTF cases have been published. We present a biopsy-proven case of NTF that is likely to have developed as a result of weightlifting activity in the gym, including repetitive trauma to the area of the lesion during the exercise known as the "barbell back squat." During this exercise, a heavy barbell was repeatedly rested on the patient's vertebral prominence at the level of C7/T1, the location where the NTF developed. Our 25-year old patient reported that he had been doing this exercise on a weekly basis for about 10 years. We believe that repetitive trauma at this location from specific weightlifting exercises may attribute to the incidence of NTF. A description of key magnetic resonance imaging characteristics and the surgical pathology of this case are provided, along with a review of current literature on trauma-related NTFs.
During CNS development, oligodendrocytes, the myelinating glia of the CNS, progress through multiple transitory stages before terminating into fully mature cells. Oligodendrocyte differentiation and ...myelination is a tightly regulated process requiring extracellular signals to converge to elicit specific translational and transcriptional changes. Our lab has previously shown that the protein kinases, Akt and mammalian Target of Rapamycin (mTOR), are important regulators of CNS myelination in vivo. mTOR functions through two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, by binding to either Raptor or Rictor, respectively. To establish whether the impact of mTOR on CNS myelination results from unique functions of mTORC1 or mTORC2 during CNS myelination, we conditionally ablated either Raptor or Rictor in the oligodendrocyte lineage, in vivo. We show that Raptor (mTORC1) is a positive regulator of developmental CNS mouse myelination when mTORC2 is functional, whereas Rictor (mTORC2) ablation has a modest positive effect on oligodendrocyte differentiation, and very little effect on myelination, when mTORC1 is functional. Also, we show that loss of Raptor in oligodendrocytes results in differential dysmyelination in specific areas of the CNS, with the greatest impact on spinal cord myelination.
T cells targeting shared oncogenic mutations can induce durable tumor regression in epithelial cancer patients. Such T cells can be detected in tumor infiltrating lymphocytes, but whether such cells ...can be detected in the peripheral blood of patients with the common metastatic epithelial cancer patients is unknown. Using a highly sensitive in vitro stimulation and cell enrichment of peripheral memory T cells from six metastatic cancer patients, we identified and isolated CD4
, and CD8
memory T cells targeting the mutated KRAS
and KRAS
variants, respectively, in three patients. In an additional two metastatic colon cancer patients, we detected CD8
neoantigen-specific cells targeting the mutated SMAD5 and MUC4 proteins. Therefore, memory T cells targeting unique as well as shared somatic mutations can be detected in the peripheral blood of epithelial cancer patients and can potentially be used for the development of effective personalized T cell-based cancer immunotherapy across multiple patients.
Adoptive T cell therapy (ACT) using ex vivo-expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate complete regression of certain human cancers. The impact of TIL phenotypes on ...clinical success of TIL-ACT is currently unclear. Using high-dimensional analysis of human ACT products, we identified a memory-progenitor CD39-negative stem-like phenotype (CD39
CD69
) associated with complete cancer regression and TIL persistence and a terminally differentiated CD39-positive state (CD39
CD69
) associated with poor TIL persistence. Most antitumor neoantigen-reactive TILs were found in the differentiated CD39
state. However, ACT responders retained a pool of CD39
stem-like neoantigen-specific TILs that was lacking in ACT nonresponders. Tumor-reactive stem-like TILs were capable of self-renewal, expansion, persistence, and superior antitumor response in vivo. These data suggest that TIL subsets mediating ACT response are distinct from TIL subsets enriched for antitumor reactivity.
The TP53 gene, encoding the critical p53 tumor suppressor, is the most commonly mutated gene in cancer. Intratumoral T cell responses to mutations occurring frequently at certain TP53 positions, ...termed hot spots, have not been systematically studied. The 8 most commonly mutated positions in TP53 were found in 33 (24%) of 140 common epithelial tumors analyzed. A TP53-specific screening assay was developed to evaluate T cell responses to these p53 neoepitopes presented though intracellular (tandem minigene) and extracellular (pulsed peptide) pathways on autologous antigen-presenting cells expressing all human leukocyte antigen (HLA) class I and II molecules. Tumor-infiltrating lymphocytes (TILs) from 11 patients recognized autologous p53 neoantigens, which accounted for 8% and 39% of all patients sequenced (n = 140) and screened (n = 28), respectively. These responses were restricted by a variety of HLA restriction elements, including common class I (A*02:01) and class II (DPB1*02:01 and DRB1*13:01) alleles. T cell receptors (TCRs) were identified from TP53 mutation-reactive helper (CD4) and cytotoxic (CD8) T cells, and TIL and TCR gene-engineered T cells recognized tumor cell lines endogenously expressing HLA and mutant TP53. Thus, the most commonly mutated gene in cancer, TP53, appears to be immunogenic and represents an attractive candidate for evaluating targeted immune cancer therapies.
The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge for the engineering of cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR ...clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8
and CD4
neoantigen-reactive tumor-infiltrating lymphocytes (TILs). Neoantigen-specific TILs exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TILs. Prospective prediction and testing of 73 NeoTCR signature-derived clonotypes demonstrated that half of the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs that target driver neoantigens and nonmutated viral or tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TILs across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy.
Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients with common epithelial cancers. This raises the question of whether ...patients with these common cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous tumors that may represent ideal targets for immunotherapy. Using high-throughput immunologic screening of mutant gene products identified via whole-exome sequencing, we identified neoantigen-reactive tumor-infiltrating lymphocytes (TIL) from 62 of 75 (83%) patients with common gastrointestinal cancers. In total, 124 neoantigen-reactive TIL populations were identified, and all but one of the neoantigenic determinants were unique. The results of
T-cell recognition assays demonstrated that 1.6% of the gene products encoded by somatic nonsynonymous mutations were immunogenic. These findings demonstrate that the majority of common epithelial cancers elicit immune recognition and open possibilities for cell-based immunotherapies for patients bearing these cancers. SIGNIFICANCE: TILs cultured from 62 of 75 (83%) patients with gastrointestinal cancers recognized neoantigens encoded by 1.6% of somatic mutations expressed by autologous tumor cells, and 99% of the neoantigenic determinants appeared to be unique and not shared between patients.
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Advancements in geospatial datasets, exposure assessment, tracking methodology, and big data/machine learning techniques provide opportunities to meet the unmet nature-exposure measurement need. ...NatureQuantTM, a new research and technology institution, was formed with this goal in mind. It recently created 2 technologies that may help overcome existing barriers in quantifying nature exposure and, in turn, expand its use for health promotion.64The first technology is the NatureScoreTM dataset and tool, which summarizes the environmental conditions at a given location to generate an overall “NatureScore” value, discussed below. The second technology is the “NatureDose” mobile app, which references NatureScoreTM values as an individual moves through time and space to generate an overall metric of nature exposure over time (Figure 1). These technologies are beginning to help researchers refine our understanding of the benefits of nature exposure and catalyze the use of nature as a health promotion tool.6
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