Jennifer H. Shin

An evidence-based review of poorly differentiated thyroid cancer

BackgroundPoorly differentiated thyroid cancer (PDTC) presents the endocrinologist and surgeon with challenges of recognition and treatment given the lack of consensus on histopathologic definition and limited literature on surgical and nonsurgical treatment.MethodsWe offer an operational pathologic definition for PDTC, which should help guide future work in this area. Poorly differentiated thyroid cancer should include insular and trabecular variants but should not include solid type lesions (included by other workers) or more differentiated tumors that may have poor prognosis such as tall cell, columnar, diffuse sclerosing, and oncocytic lesions. Systematic evidence-based literature reviews focusing on two questions were carried out: (1) is PDTC associated with an intermediate prognosis relative to anaplastic and WDTC? and (2) What are the postoperative treatment options for poorly differentiated thyroid cancer?ConclusionsWe have found level IV evidence that PDTC is intermediate between WDTC and anaplastic cancers in terms of prognosis. It represents a disease where appropriate administration of aggressive treatment not typically necessary for routine WDTC and not effective for anaplastic disease may uniquely result in substantial benefit. Limited level IV data show conflicting results regarding 131I treatment benefit. Given lack of morbidity and potential for benefit, we recommend that 131I therapy be considered in all patients postoperatively. Recommendation regarding external beam radiotherapy (XRT) is based primarily on extrapolation from studies in forms of poor-prognosis WDTC where substantial data exist regarding treatment benefit. We recommend that external beam treatment be considered in all patients with PDTC with T3 tumors without distant metastasis, all patients with T4 tumors, and all patients with regional lymph node involvement.

Interleukin-17A inhibits adipocyte differentiation in human mesenchymal stem cells and regulates pro-inflammatory responses in adipocytes

The immune system is closely linked to human metabolic diseases. Serum levels of IL-6 increase with obesity and insulin resistance. Not only does IL-6 decrease the insulin sensitivity of human cells such as adipocytes, but it also regulates the lineage commitment of naïve T cells into interleukin (IL)-17A-producing CD4(+) T (Th17) cells. Although IL-17A exerts a variety of effects on somatic tissues, its functional role in human adipocytes has not been identified. In this work, we show that IL-17A inhibits adipocyte differentiation in human bone marrow mesenchymal stem cells (hBM-MSCs), while promoting lipolysis of differentiated adipocytes. We find that IL-17A increases both mRNA and protein secretion of IL-6 and IL-8 during adipocyte differentiation in hBM-MSCs. IL-17A up-regulates cyclooxygenase (COX)-2 gene expression and thereby increases the level of prostaglandin (PG) E(2) in differentiated adipocyes. The suppression of anti-adipogenic PGE(2) by COX inhibitors such as aspirin and NS-398 partially blocked the effect of IL-17A on adipocyte differentiation in hBM-MSCs. Therefore, IL-17A exhibits its inhibitory effect in part via the COX-2 induction in differentiated adipocytes. In addition, treatment with anti-IL-17A antibody neutralizes IL-17A-mediated effects on adipocyte differentiation and function. These results suggest that IL-17A plays a regulatory role in both the metabolic and inflammatory processes of human adipocytes, similar to other pro-inflammatory cytokines such as IL-1, IFNgamma, and TNFalpha.

Differential responses of human liver cancer and normal cells to atmospheric pressure plasma

When treated by atmospheric pressure plasma, human liver cancer cells (SK-HEP-1) and normal cells (THLE-2) exhibited distinctive cellular responses, especially in relation to their adhesion behavior. We discovered the critical threshold voltage of 950 V, biased at the electrode of the micro-plasma jet source, above which SK-HEP-1 started to detach from the substrate while THLE-2 remained intact. Our mechanical and biochemical analyses confirmed the presence of intrinsic differences in the adhesion properties between the cancer and the normal liver cells, which provide a clue to the differential detachment characteristics of cancer and normal cells to the atmospheric pressure plasma.

Management of invasive well-differentiated thyroid cancer: an American Head and Neck Society consensus statement. AHNS consensus statement.

Invasive differentiated thyroid cancer (DTC) is relatively frequent, yet there is a paucity of specific guidelines devoted to its management. The Endocrine Committee of the American Head and Neck Society (AHNS) convened a panel to provide clinical consensus statements based on review of the literature, synthesized with the expert opinion of the group.

Plasma effects on subcellular structures

Atmospheric pressure helium plasma treated human hepatocytes exhibit distinctive zones of necrotic and live cells separated by a void. We propose that plasma induced necrosis is attributed to plasma species such as oxygen radicals, charged particles, metastables and/or severe disruption of charged cytoskeletal proteins. Interestingly, uncharged cytoskeletal intermediate filaments are only minimally disturbed by plasma, elucidating the possibility of plasma induced electrostatic effects selectively destroying charged proteins. These bona fide plasma effects, which inflict alterations in specific subcellular structures leading to necrosis and cellular detachment, were not observed by application of helium flow or electric field alone.

Shape memory alloy-based small crawling robots inspired by C. elegans

Inspired by its simple musculature, actuation and motion mechanisms, we have developed a small crawling robot that closely mimics the model organism of our choice: Caenorhabditis elegans. A thermal shape memory alloy (SMA) was selected as an actuator due to the similarities of its properties to C. elegans muscles. Based on the anatomy of C. elegans, a 12-unit robot was designed to generate a sinusoidal undulating motion. Each body unit consisting of a pair of SMA actuators is serially connected by rigid links with an embedded motion control circuit. A simple binary operation-based motion control mechanism was implemented using a microcontroller. The assembled robot can execute C. elegans-like motion with a 0.17 Hz undulation frequency. Its motion is comparable to that of a real worm.

Physicochemical control of adult stem cell differentiation: shedding light on potential molecular mechanisms.

Realization of the exciting potential for stem-cell-based biomedical and therapeutic applications, including tissue engineering, requires an understanding of the cell-cell and cell-environment interactions. To this end, recent efforts have been focused on the manipulation of adult stem cell differentiation using inductive soluble factors, designing suitable mechanical environments, and applying noninvasive physical forces. Although each of these different approaches has been successfully applied to regulate stem cell differentiation, it would be of great interest and importance to integrate and optimally combine a few or all of the physicochemical differentiation cues to induce synergistic stem cell differentiation. Furthermore, elucidation of molecular mechanisms that mediate the effects of multiple differentiation cues will enable the researcher to better manipulate stem cell behavior and response.

Nanowire-integrated microfluidic devices for facile and reagent-free mechanical cell lysis

Cell lysis is an essential task for the detection of intracellular components. In this work, we introduce novel microfluidic devices integrated with patterned one-dimensional nanostructure arrays for facile and high-throughput mechanical cell lysis. The geometry of the hydrothermally grown ZnO nanowires, characterised by sharp tips and high aspect ratios, aids in anchoring the cell and tearing the plasma membrane, enabling simple and highly efficient extraction of cellular proteins and nucleic acids. This method lyses cells more effectively than conventional chemical lysis methods with simpler equipment and a shorter processing time.

Novel participation of transglutaminase-2 through c-Jun N-terminal kinase activation in sphingosylphosphorylcholine-induced keratin reorganization of PANC-1 cells

Sphingosylphosphorylcholine (SPC) is found at increased levels in the malignant ascites of tumor patients and induces perinuclear reorganization of keratin 8 (K8) filaments that contribute to the viscoelasticity of metastatic cancer cells. In this study, we investigated the role and molecular mechanisms of Tgase-2 in SPC-induced K8 phosphorylation and perinuclear reorganization in PANC-1 cells (PAN(WT)), and in PANC-1 cells that stably expressed shTgase-2 or Tgase-2 (PAN(shTg2) and PAN(Tg2)). SPC induces the expression of Tgase-2 in a time- and dose-dependent manner. Gene silencing of Tgase-2 or cystamine suppressed the SPC-induced phosphorylation and perinuclear reorganization of K8 and suppressed the SPC-induced migration of PANC-1 cells. An inhibitor of c-Jun N-terminal kinase (JNK), SP600125, suppressed the SPC-induced phosphorylation of serine 431 in K8 and keratin reorganization. Next, we examined the effect of Tgase-2 on JNK activation of serine 431 phosphorylation in K8. Tgase-2 gene silencing suppressed the expression of active form JNK (pJNK). Constitutive or tetracyclin-induced conditional expression of Tgase-2 increased the levels of pJNK. Tgase-2 was coimmunoprecipitated with K8 and JNK. In addition, K8 was coimmunoprecipitated with Tgase-2 and JNK. JNK was also coimmunoprecipitated with K8 and Tgase-2. Overall, these results suggest that Tgase-2 is involved in SPC-induced phosphorylation and perinuclear reorganization of K8 by activating JNK and forming a triple complex with K8 and JNK. Therefore, SPC-induced Tgase-2 might be a new target for modulating keratin reorganization, metastasis of cancer cells and JNK activation.

Cellular Contraction and Polarization Drive Collective Cellular Motion

Coordinated motions of close-packed multicellular systems typically generate cooperative packs, swirls, and clusters. These cooperative motions are driven by active cellular forces, but the physical nature of these forces and how they generate collective cellular motion remain poorly understood. Here, we study forces and motions in a confined epithelial monolayer and make two experimental observations: 1) the direction of local cellular motion deviates systematically from the direction of the local traction exerted by each cell upon its substrate; and 2) oscillating waves of cellular motion arise spontaneously. Based on these observations, we propose a theory that connects forces and motions using two internal state variables, one of which generates an effective cellular polarization, and the other, through contractile forces, an effective cellular inertia. In agreement with theoretical predictions, drugs that inhibit contractility reduce both the cellular effective elastic modulus and the frequency of oscillations. Together, theory and experiment provide evidence suggesting that collective cellular motion is driven by at least two internal variables that serve to sustain waves and to polarize local cellular traction in a direction that deviates systematically from local cellular velocity.