Targeting Tumor Microenvironment Akt Signaling Represents a Potential Therapeutic Strategy for Aggressive Thyroid Cancer.

Effects of the tumor microenvironment (TME) stromal cells on progression in thyroid cancer are largely unexplored. Elucidating the effects and underlying mechanisms may facilitate the development of targeting therapy for aggressive cases of this disease. In this study, we investigated the impact of TME stromal cells on cancer stem-like cells (CSCs) in patient-relevant contexts where applying in vitro assays and xenograft models uncovered contributions of TME stromal cells to thyroid cancer progression. We found that TME stromal cells can enhance CSC self-renewal and invasiveness mainly via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. The disruption of Akt signaling could diminish the impact of TME stromal cells on CSC aggressiveness in vitro and reduce CSC tumorigenesis and metastasis in xenografts. Notably, disrupting Akt signaling did not cause detectable alterations in tumor histology and gene expression of major stromal components while it produced therapeutic benefits. In addition, using a clinical cohort, we discovered that papillary thyroid carcinomas with lymph node metastasis are more likely to have elevated Akt signaling compared with the ones without metastasis, suggesting the relevance of Akt-targeting. Overall, our results identify PI3K/Akt pathway-engaged contributions of TME stromal cells to thyroid tumor disease progression, illuminating TME Akt signaling as a therapeutic target in aggressive thyroid cancer.

Subpopulations of cancer stem cells found in papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer and while it has a generally good prognosis, tumor recurrence remains a major clinical challenge. Studying laboratory cell lines as well as clinical specimens indicate that PTC may follow the cancer stem cell (CSC) model. However, CSC characteristics relevant in PTC initiation and progression remain largely unknown. Here we studied a population of sphere-growing tumor cells isolated from primary cultures of clinical PTC. These sphere-growing cells consisted of aldehyde dehydrogenase positive (ALDH+) and ALDH negative (ALDH-) cell subpopulations and demonstrated a hierarchical pattern of cell division. Using combinations of selective depletion, specific inhibition and cell sorting, we found that both subpopulations of the sphere cells were able to self-renew and initiate xenograft tumors independently, and fulfilled the definition of CSC. Importantly, when the subpopulations functioned together, the cancer-initiation efficiency and the xenograft tumor progression were significantly enhanced compared to either subpopulation alone. These data revealed crucial roles of ALDH- CSC in PTC biology and suggested that CSC subpopulations function cooperatively to control PTC initiation and progression. Together, our study indicates that CSC subpopulations isolated from clinical specimens offer unprecedented opportunities for investigating PTC pathogenesis and developing effective therapies.

Microvascular replantation of a composite facial avulsion in a 24-month-old child after dog bite.

Dog bite injuries are common sources of morbidity with an estimated incidence of 4.5 million bites per year with over 350,000 requiring treatment in the emergency room. Children under the age of 14 are most likely to be affected with a peak age of 5-9 years old. We report a case of a 24-month-old female who sustained a large composite facial avulsion injury from a pit bull dog bite. The avulsed tissue involved a substantial portion of the patient's mid-face, including the entire soft tissue of the nose, upper lip, part of the left cheek, and left oral commissure. Artery-only microvascular replantation was performed because no recipient vein could be identified from the facial defect. Medicinal leech therapy was used for eight days postoperatively to prevent venous congestion. The patient experienced significant blood loss due to leech therapy and required nearly 29 L of blood product replacement. At the last follow up of 8 months postoperatively, the patient was recovering well with significant improvement in function and cosmesis of the mid-face. This case describes a successful artery-only replantation of an avulsive bite injury to the face of a young child. Despite the technical difficulty of cases such as this one, microvascular replantation should be attempted because when successful it provides a superior cosmetic and functional result to other reconstructive techniques.

Cancer stem cell self-renewal as a therapeutic target in human oral cancer.

Tumor recurrence following treatment remains a major clinical challenge in oral cavity cancer. Cancer stem cells (CSCs) have been isolated from human oral cancers and been considered as the driving force of tumor recurrence and metastasis. However, it still remains unclear whether targeting CSCs in oral cancer is a clinically relevant strategy to combat cancer recurrence and metastasis. Here, using clinical cancer specimens and patient-derived xenografts, we show that the self-renewal regulator BMI1 is highly expressed in CSCs of oral cavity squamous cell carcinoma. Inhibition of BMI1 decreases oral CSCs' self-renewal and tumor-initiating potential. Treatment of pre-established human oral cancer xenografts with a BMI1 inhibitor resulted in abrogation of tumor progression and reduced the frequency of CSCs in the xenografts. Remarkably, the BMI1 inhibitor has therapeutic effects in cisplatin-resistant tumors and can reduce metastases initiated by circulating CSCs. Mechanistically, BMI1-inhibition leads to oral CSC necroptotic cell death, which underlies the self-renewal impairment after inhibiting BMI1. Our data provide a pre-clinical proof-of-concept that targeting BMI1-related CSC self-renewal is a clinically relevant anti-cancer therapy in human oral cavity squamous cell carcinoma.

Performance variability on perceptual discrimination tasks in profoundly deaf adults with cochlear implants.

OBJECTIVES: The purpose of this study was to evaluate performance on two challenging listening tasks, talker and regional accent discrimination, and to assess variables that could have affected the outcomes. STUDY DESIGN: A prospective study using 35 adults with one cochlear implant (CI) or a CI and a contralateral hearing aid (bimodal hearing) was conducted. Adults completed talker and regional accent discrimination tasks. METHODS: Two-alternative forced-choice tasks were used to assess talker and accent discrimination in a group of adults who ranged in age from 30 years old to 81 years old. RESULTS: A large amount of performance variability was observed across listeners for both discrimination tasks. Three listeners successfully discriminated between talkers for both listening tasks, 14 participants successfully completed one discrimination task and 18 participants were not able to discriminate between talkers for either listening task. Some adults who used bimodal hearing benefitted from the addition of acoustic cues provided through a HA but for others the HA did not help with discrimination abilities. Acoustic speech feature analysis of the test signals indicated that both the talker speaking rate and the fundamental frequency (F0) helped with talker discrimination. For accent discrimination, findings suggested that access to more salient spectral cues was important for better discrimination performance. CONCLUSIONS: The ability to perform challenging discrimination tasks successfully likely involves a number of complex interactions between auditory and non-auditory pre- and post-implant factors. To understand why some adults with CIs perform similarly to adults with normal hearing and others experience difficulty discriminating between talkers, further research will be required with larger populations of adults who use unilateral CIs, bilateral CIs and bimodal hearing.

Local Intraluminal Irrigation With Argatroban During Free Flap Repair in a Patient With Heparin-Induced Thrombocytopenia.

OBJECTIVE: This study describes a case of a successful free flap repair using argatroban for local intraluminal irrigation as a substitute to heparin in a patient with heparin-induced thrombocytopenia. METHODS: Case report and review of literature. RESULTS: The patient had an uneventful postoperative course, and the free flap survived without complications. CONCLUSIONS: The use of argatroban during microvascular surgery is likely to be safe and simple and may be effective in preventing micro-thrombotic complications during microvascular surgery, and it should be considered as an alternative to heparinized saline for local intraluminal irrigation.

Identification of acoustically similar and dissimilar vowels in profoundly deaf adults who use hearing aids and/or cochlear implants: some preliminary findings.

PURPOSE: In this study, the authors examined the effects of aging and residual hearing on the identification of acoustically similar and dissimilar vowels in adults with postlingual deafness who use hearing aids (HAs) and/or cochlear implants (CIs). METHOD: The authors used two groups of acoustically similar and dissimilar vowels to assess vowel identification. Also, the Consonant-Nucleus-Consonant Word Recognition Test (Peterson & Lehiste, 1962) and sentences from the Hearing in Noise Test (Nilsson, Soli, & Sullivan, 1994) were administered. Forty CI recipients with postlingual deafness (ages 31-81 years) participated in the study. RESULTS: Acoustically similar vowels were more difficult to identify than acoustically dissimilar vowels. With increasing age, performance deteriorated when identifying acoustically similar vowels. Vowel identification was also affected by the use of a contralateral HA and the degree of residual hearing prior to implantation. Moderate correlations were found between speech perception and vowel identification performance. CONCLUSIONS: Identification performance was affected by the acoustic similarity of the vowels. Older adults experienced more difficulty identifying acoustically similar confusable vowels than did younger adults. The findings might lend support to the ease of language understanding model (Ronnberg, Rudner, Foo, & Lunner, 2008), which proposes that the quality and perceptual robustness of acoustic input affects speech perception.

Cochlear implants and spoken language processing abilities: review and assessment of the literature.

Cochlear implants (CIs) process sounds electronically and then transmit electric stimulation to the cochlea of individuals with sensorineural deafness, restoring some sensation of auditory perception. Many congenitally deaf CI recipients achieve a high degree of accuracy in speech perception and develop near-normal language skills. Post-lingually deafened implant recipients often regain the ability to understand and use spoken language with or without the aid of visual input (i.e. lip reading). However, there is wide variation in individual outcomes following cochlear implantation, and some CI recipients never develop useable speech and oral language skills. The causes of this enormous variation in outcomes are only partly understood at the present time. The variables most strongly associated with language outcomes are age at implantation and mode of communication in rehabilitation. Thus, some of the more important factors determining success of cochlear implantation are broadly related to neural plasticity that appears to be transiently present in deaf individuals. In this article we review the expected outcomes of cochlear implantation, potential predictors of those outcomes, the basic science regarding critical and sensitive periods, and several new research directions in the field of cochlear implantation.