"Be ready against cancer, now": direct-to-consumer advertising for genetic testing

A recent addition to the debate about the benefits and harms of direct-to-consumer (DTC) advertising of medicines and pharmaceuticals is a growing critique of DTC marketing and sale of genetic tests. Academic and policy literatures exploring this issue have, however, tended to focus on the sale of genetic tests, paying rather less attention to the particular implications of advertising. The globalization of broadcast media and ever increasing access to the Internet mean that public exposure to advertising for medical technologies is a reality that national regulatory bodies will be hard pressed to constrain. Working through a case study detailing Myriad Genetics' 2002 pilot advertising campaign for their BRACAnalysis genetic susceptibility test for hereditary breast and ovarian cancer, this paper highlights some of the diverse and often overlooked and unregulated approaches to DTC advertising, and the associated social, ethical and policy implications.     

Increased lead uptake and inhibition of ALAD-activity in isolated rat hepatocytes incubated with lead-diethyldithiocarbamate complex

Dithiocarbamates can form lipid soluble complexes with lead and are known to markedly increase tissue uptake of lead and potentiate toxic effects of lead in rats. Cellular effects of the interactions between lead and diethyldithiocarbamate were studied in primary cultures of rat hepatocytes. The cells were incubated with lead acetate (PbAc) or lead-diethyldithiocarbamate complex (Pb(DTC)2), labelled with 203Pb. The lipid soluble Pb(DTC)2 was rapidly taken up in the cells and after 30 min incubation the cellular levels of lead were approximately 40 times higher in cells incubated with Pb(DTC)2 than in cells incubated with a similar concentration of PbAc. The maximal cellular uptake of lead was reached after 4 h incubation with Pb(DTC)2, while incubation with PbAc caused a slow continuously increasing uptake of lead during the 20 h incubation. The enzyme delta-aminolevulinic acid dehydratase (ALAD) was inhibited to a much higher extent by Pb(DTC)2 compared to PbAc after incubations with similar concentrations of lead. Maximal inhibition of ALAD activity was reached at a cellular concentration of 0.5-1 nmol Pb/mg protein, irrespective of which form of lead was used in the incubation. Pb(DTC)2 was shown to inhibit ALAD activity also in vitro when incubated with purified ALAD enzyme. The rapid and high intracellular uptake and cellular response of Pb(DTC)2, shown in the present study, may explain the drastic effects of dithiocarbamates on lead distribution and toxicity previously shown in vivo.     

mig-38, a novel gene that regulates distal tip cell turning during gonadogenesis in C. elegans hermaphrodites

In Caenorhabditis elegans gonad morphogenesis, the final U-shapes of the two hermaphrodite gonad arms are determined by migration of the distal tip cells (DTCs). These somatic cells migrate in opposite directions on the ventral basement membrane until specific extracellular cues induce turning from ventral to dorsal and then centripetally toward the midbody region on the dorsal basement membrane. To dissect the mechanism of DTC turning, we examined the role of a novel gene, F40F11.2/mig-38, whose depletion by RNAi results in failure of DTC turning so that DTCs continue their migration away from the midbody region. mig-38 is expressed in the gonad primordium, and expression continues throughout DTC migration where it acts cell-autonomously to control DTC turning. RNAi depletion of both mig-38 and ina-1, which encodes an integrin adhesion receptor, enhanced the loss of turning phenotype indicating a genetic interaction between these genes. Furthermore, the integrin-associated protein MIG-15/Nck-interacting kinase (NIK) works with MIG-38 to direct DTC turning as shown by mig-38 RNAi with the mig-15(rh80) hypomorph. These results indicate that MIG-38 enhances the role of MIG-15 in integrin-dependent DTC turning. Knockdown of talin, a protein that is important for integrin activation, causes the DTCs to stop migration prematurely. When both talin and MIG-38 were depleted by RNAi treatment, the premature stop phenotype was suppressed. This suppression effect was reversed upon additional depletion of MIG-15 or its binding partner NCK-1. These results suggest that both talin and the MIG-15/NCK-1 complex promote DTC motility and that MIG-38 may act as a negative regulator of the complex. We propose a model to explain the dual role of MIG-38 in motility and turning.     

Active Surveillance for Low-Risk Differentiated Thyroid Cancer

Less aggressive treatment options, including hemithyroidectomy and active surveillance, have been accepted as treatment options for low-risk small, differentiated thyroid carcinoma (DTC). Multiple studies have shown a low rate of cancer growth and lymph node metastases and no evidence of distant metastases during active surveillance of low-risk small DTC. However, not all patients with low -risk small DTC are ideal or appropriate candidate for active surveillance. Patients with thyroid cancer adjacent to either the trachea or recurrent laryngeal nerve or those with evidence of extrathyroidal extension, a high-risk molecular profile, lymph node, or distant metastases are considered inappropriate candidates for active surveillance. In addition, there are other essential factors that clinicians should consider while recommending active surveillance, including patient financial and insurance status; availability of high-quality neck ultrasounds and experienced radiologists, endocrinologists, and surgeons; and patient preference, level of anxiety, and willingness to undergo prolonged surveillance and follow-up imaging.     

Sleep Quality of Patients with Differentiated Thyroid Cancer

Objective

We aimed to measure prevalence of sleep disturbance in patients with differentiated thyroid cancer (DTC) by calculating Pittsburgh Sleep Quality Index (PSQI), and compare these data with patients with benign thyroid nodules or normal participants.

Methods

Three groups of patients participated in this cross-sectional study. In the first group, 162 patients with DTC received total thyroidectomy, and then ¹³¹I therapy. The second group consisted of 84 patients with benign thyroid nodules, who received partial thyroidectomy. The third group was 78 normal healthy control cases. PSQI was used to assess the sleep quality. Inter-group differences were analyzed by Kruskal-Wallis test or independent samples T test. χ² test was also used to check prevalence differences of poor sleep quality among the groups. Differences of PSQI score and poor sleep quality prevalence before and after ¹³¹I therapy in the same group of DTC participants were analyzed by paired T test and Mcnemar''s test.

Results

Higher PSQI score (7.59 ± 4.21) and higher rate of poor sleep quality (54.32%) were shown in DTC patients than in any other group. After ¹³¹I therapy, PSQI score and prevalence of poor sleep quality in DTC patients increased significantly to 8.78 ± 4.72 and 70.99%. Then DTC patients were divided into two subgroups based on their metastatic status. DTC patients with metastasis (87/162 cases, 53.70%) had significantly higher PSQI score (10.87 ± 5.18) and higher prevalence of poor sleep quality (79.31%).

Conclusion

DTC patients suffer from sleep disturbance, ¹³¹I therapy and awareness of metastatic status could worsen sleep problem. Psychological fear of cancer, nuclear medicine therapy and metastasis could be one major underlying reason. Longitude and interventional studies are necessary for further investigations.     

Combination of diethyldithiocarbamate with 12-O-tetradecanoyl phorbol-13-acetate inhibits the growth of human myeloid leukemia HL-60 cells in vitro and in xenograft model

ABSTRACT

12-O-tetradecanoylphorbol-13-acetate (TPA), is a major active constituent of the seed oil of Croton tiglium L., has pharmacological activity for the treatment of acute myeloid leukemia patients. Diethyldithiocarbamate (DTC) is a potent inhibitor of NF-κB show activity of anticancer. In this study, we determined the effect of DTC and TPA in combination on HL-60 cells cultured in vitro and in vivo. In this study, we have shown that DTC and TPA synergistically inhibited the growth of HL-60 cells and strongly induced apoptosis in the cells. Mechanistic studies showed that the combined effects of DTC and TPA were associated with a decrease in Bcl-2. The animal experiment showed that the combination of DTC and TPA more potently inhibited the growth of HL-60 tumors than either agent alone. Our results indicate that the administration of TPA and DTC in combination may be an effective strategy for inhibiting the growth of acute myeloid leukemia cells.     

Mutations affecting symmetrical migration of distal tip cells in Caenorhabditis elegans.

The rotational symmetry of the Caenorhabditis elegans gonad arms is generated by the symmetrical migration of two distal tip cells (DTCs), located on the anterior and posterior ends of the gonad primordium. Mutations that cause asymmetrical migration of the two DTCs were isolated. All seven mutations were recessive and assigned to six different complementation groups. vab-3(k121) and vab-3(k143) affected anterior DTC migration more frequently than posterior, although null mutants showed no bias. The other five mutations, mig-14(k124), mig-17(k113), mig-18(k140), mig-19(k142), and mig-20(k148), affected posterior DTC migration more frequently than anterior. These observations imply that the migration of each DTC is regulated differently. mig-14 and mig-19 also affected the migration of other cells in the posterior body region. Four distinct types of DTC migration abnormalities were defined on the basis of the mutant phenotypes. vab-3; mig-14 double mutants exhibited the types of DTC migration defects seen for vab-3 single mutants. Combination of mig-17 and mig-18 or mig-19, which are characterized by the same types of posterior DTC migration defects, exhibited strong enhancement of anterior DTC migration defects, suggesting that they affect the same or parallel pathways regulating anterior DTC migration.     

Estrogen Receptor and HER2 Status on Disseminated Tumor Cells and Primary Tumor in Patients with Early Breast Cancer

BACKGROUND: We evaluated both estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status on disseminated tumor cells (DTCs) in the bone marrow of 54 patients with early breast cancer and compared these with the corresponding primary tumor (PT). MATERIALS AND METHODS: Bone marrow aspirates were obtained at the time of first surgery, and ER and HER2 status on DTCs was assessed simultaneously by immunocytochemistry using a triple fluorescence staining method. RESULTS: The median number of DTCs was 13 (range 1-95). The concordance rate between ER status on DTC and PT was 74%. Patients with an ER-positive PT were significantly more likely to have at least one ER-positive DTC (34 out of 42) than patients with an ER-negative PT (6 out of 12; P = .031). Thirty-nine (93%) of the 42 patients with ER-positive PT had at least one ER-negative DTC. The concordance rate between HER2 status on DTC and PT was 52%. The probability of having at least one HER2-positive DTC was not related to the HER2 status of the PT (P = 0.56). Twenty-two (46%) of the 48 patients with a HER2-negative PT had at least one HER2-positive DTC. All the six patients with a HER2-positive PT had at least one HER2-negative DTC. CONCLUSION: Taken together, our study confirms that ER and/or HER2 status may differ between DTC and PT. This discordance could be important for patients lacking ER or HER2 expression on the PT but showing ER-positive or HER2-positive DTC because they might benefit from an endocrine and/or HER2-targeted therapy.     

Detection and molecular characterisation of disseminated tumour cells: Implications for anti-cancer therapy

Haematogenous distant metastasis is the leading cause of cancer-related death in solid tumours. By applying sensitive immunocytochemical and molecular assays, disseminated tumour cells (DTC) in bone marrow (BM) can be detected in 20–40% of cancer patients without any clinical or even histopathological signs of metastasis, and the presence of these DTC at primary diagnosis predicts the subsequent occurrence of overt metastases in bone and other organs. The detection and characterisation of DTC in BM may lead to a better understanding of the biology initiating metastatic spread in cancer patients and will eventually contribute to the development of more effective strategies to eliminate DTC. In this review, we will therefore discuss the detection and characterisation of DTC in the light of new therapeutic strategies targeting tumour-associated molecules and signalling pathways.     

Identification and Kinetic Characterization of HtDTC, The Mitochondrial Dicarboxylate–Tricarboxylate Carrier of Jerusalem Artichoke Tubers

Jerusalem artichoke (Helianthus tuberosus L.) tubers were reported to be tolerant to cold and freezing. The aim of this study was to perform a kinetic characterization of the mitochondrial dicarboxylate–tricarboxylate carrier (HtDTC) and to assess a possible involvement of this carrier in the cold tolerance of tubers. The HtDTC was purified from isolated mitochondria by sequential chromatography on hydroxylapatite/celite and Matrex Gel Orange A. SDS gel electrophoresis of the purified fraction showed a single polypeptide band with an apparent molecular mass of 31.6 kDa. A polyclonal antibody raised against the tobacco DTC cross-reacted with the purified protein on Western blot analysis. In gel trypsin, digestion of the purified HtDTC yielded peptides that exhibited strong amino acid sequence similarity to previously identified plant DTCs. Furthermore, using degenerate primers, a portion of the Htdtc cDNA was amplified and sequenced; this cDNA encoded for a protein with high sequence similarity to known plant homolog DTCs. When reconstituted in liposomes loaded with dicarboxylate (2-oxoglutarate, malate, malonate, succinate, and maleate) or tricarboxylate anions (citrate, trans-aconitate, and isocitrate), the purified HtDTC transported all these anions in exchange with external [¹⁴C]2-oxoglutarate. A kinetic characterization of HtDTC was performed: (a) the half-saturation constant K _m and the V _max at 25^∘C of the 2-oxoglutarate/2-oxoglutarate exchange by reconstituted HtDTC were found to be 360 μM and 10.9 μmol/(min mg protein), respectively; (b) the activation energy E _a of the succinate/2-oxoglutarate exchange by the reconstituted HtDTC was found to be 50.7 kJ/mol constant between −5 and 35^∘C. Similarly, the activation energy E _a of succinate respiration of isolated Jerusalem artichoke mitochondria, measured between −2 and 35^∘C, was shown to be constant (65.3 kJ/mol). The physiological relevance of kinetic properties and temperature dependence of transport activities of HtDTC is discussed with respect to the cold tolerance ability of Jerusalem artichoke tubers.     

Distinct functional roles of Akt isoforms for proliferation, survival, migration and EGF-mediated signalling in lung cancer derived disseminated tumor cells

Single disseminated tumor cells (DTC) can be detected in the bone marrow (BM) from 20% to 60% of patients with various tumors including non-small cell lung cancer (NSCLC). Detection of DTC in the BM of NSCLC patients is associated with poor prognosis and may be responsible for metastatic relapse. However, the functional properties of DTC are widely unknown. Here, we performed the first functional analysis of DTC focusing on the activation of the PI3K/Akt signalling pathway and the functional roles of Akt isoforms. In vitro kinase assays revealed a high activity of Akt3 in NSCLC-derived DTC. Proliferation and survival of DTC was reduced by depletion of Akt3 and to a lesser extend by Akt1, but not after depletion of Akt2. The major effect of Akt3 on the proliferation of DTC was associated with an Akt3-mediated regulation of both, cyclin D1 and cyclin D3, whereas Akt1 regulated the expression of cyclin D1 only. In contrast all three Akt isoforms, especially Akt2, were involved in the regulation of migration. Analysis of signalling events downstream of distinct Akt isoforms revealed that expression levels of urokinase-type plasminogen activator and its receptor were decreased after knockdown of Akt1 and Akt3. In addition, EGF-stimulated proliferative and anti-apoptotic signals are mediated by Akt1 and Akt3 in DTC. Finally, by immunofluorescence staining of primary DTC from BM samples of lung cancer patients, pAkt(S473) and Akt3 positive DTC were detected in vivo. Our data demonstrate that Akt1 and notably Akt3 regulate proliferation, survival, migration and EGF-mediated signal transduction in NSCLC-derived DTC.     

Chondroitin acts in the guidance of gonadal distal tip cells in C. elegans

In Caenorhabditis elegans hermaphrodites, the U-shaped gonad arms are formed by directed migration of the gonadal distal tip cells (DTCs). The stereotyped pattern of DTC migration is carefully controlled by extracellular and cell surface molecules during larval development. Here we report that two proteins, SQV-5 (chondroitin synthase) and its cofactor MIG-22 (chondroitin polymerizing factor), are required for chondroitin biosynthesis and are essential for the dorsally guided migration of DTCs. We found that MIG-22 is expressed in migrating DTCs, hypodermal seam cells, developing vulva and oocytes. The expression of SQV-5 or MIG-22 in both DTCs and hypodermis rescued the DTC migration defects of the relevant mutants more efficiently than when they were expressed in either single tissue. Furthermore, the expression of SQV-5 by the mig-22 promoter significantly rescued sqv-5 mutants, implying that these two proteins act in the same tissues and that chondroitin proteoglycans produced in both of these tissues are required for DTC migration. The DTC migration defects caused by sqv-5 or mig-22 mutations were partially suppressed in the anterior and enhanced in the posterior DTCs in unc-6, unc-5 or unc-40 mutant backgrounds, suggesting that chondroitin proteoglycans play roles in the UNC-6/netrin-dependent guidance of DTCs.     

A pilot study of diethyldithiocarbamate in patients with acquired immune deficiency syndrome (AIDS) and the AIDS-related complex

We investigated the use of diethyldithiocarbamate (DTC, or Imuthiolr, Merieux Institute) as a therapeutic agent in patients with Acquired Immune Deficiency Syndrome (AIDS) and AIDS-Related Complex (ARC). Patients were prospectively stratified and randomized to receive DTC 200 mg/m2 intravenously weekly for 16 weeks or no therapy, followed by crossover to the opposite arm for an equal period. Forty-four patients were entered and forty were evaluable. There was a statistically significant decrease in symptoms in the DTC treated patients compared to the controls (p = .002). There was a significant improvement in lymphadenopathy in the treated patients compared to the controls (p = .005). One patient showed disappearance of splenomegaly, one clearing of antifungal agent-resistant perianal moniliasis, and one clearing of hairy leukoplakia. No significant differences in progression were noted. No changes were seen in any of the immunological parameters measured. There was no significant toxicity. Because of the changes in symptoms and in lymphadenopathy, we suggest that further study of DTC, both alone and in combination with other agents, may be indicated.     

COVID-19 Outcomes of Patients With Differentiated Thyroid Cancer: A Multicenter Los Angeles Cohort Study

ObjectiveCancer may be a risk factor for worse outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections. However, there is a significant variability across cancer types in the extent of disease burden and modalities of cancer treatment that may impact morbidity and mortality from coronavirus disease-19 (COVID-19). Therefore, we evaluated COVID-19 outcomes in patients with a differentiated thyroid cancer (DTC) history.MethodsThis is a retrospective cohort study of patients with a history of DTC and SARS-CoV2 infection from 2 academic Los Angeles healthcare systems. Demographic, thyroid cancer, and treatment data were analyzed for associations with COVID-19 outcomes.ResultsOf 21 patients with DTC and COVID-19, 8 (38.1%) were hospitalized and 2 (9.5%) died from COVID-19. Thyroid cancer initial disease burden and extent, treatment, or current response to therapy (eg, excellent vs incomplete) were not associated with COVID-19 severity in DTC patients. However, older age and the presence of a comorbidity other than DTC were significantly associated with COVID-19 hospitalization (P = .047 and P = .024, respectively). COVID-19–attributed hospitalization and mortality in DTC patients was lower than that previously reported in cancer patients, although similar to patients with nonthyroid malignancies in these centers.ConclusionThese data suggest that among patients with DTC, advanced age and comorbid conditions are significant contributors to the risk of hospitalization from SARS-CoV2 infection, rather than factors associated with thyroid cancer diagnosis, treatment, or disease burden. This multicenter report of clinical outcomes provides additional data to providers to inform DTC patients regarding their risk of COVID-19.     

Direct-to-consumer testing: if consumers are not anxious,why are policymakers?

Direct-to-consumer genetic testing continues to receive significant attention from both the popular press and policymakers. While the demand for these services has not, to date, been significant, it nevertheless seems likely that more and more individuals will be accessing DTC services. As a result, commentators have suggested that the DTC industry requires more oversight. A common rationale for policy action is that DTC services might cause undue anxiety. However, emerging evidence suggests that this is not the case. Indeed, it appears that genetic risk information has little impact on individual behavior or anxiety levels. Though more research is clearly needed, this type of research should inform the regulatory response to DTC services.     

Sodium diethyldithiocarbamate is a stimulating agent of immunity]

A single dose of DTC was administered, in a dose-range from 0.6 mg/kg to 25 mg/kg, to mice immunized with 10(8) sheep red cells (SRC). All doses strongly enhanced plaque-forming spleen cell (PFC) responses, when given either 18 h before, simultaneously to, 6 h or 24 h after SRC immunization. However, the higher levels of immunostimulation were attained by DTC doses above 5 mg/kg. DTC-induced immunopotentiation was not accompanied by untoward effects, such as acute toxicity, splenomegalia or modifcations in counts of viable spleen lymphocytes.     

Sodium diethyldithiocarbamate protects against the MPTP-induced inhibition of immune responses in mice

The effects of 1-methyl-4-phenyl - 1,2,3,6-tetrahydropyridine (MPTP) on immune parameters, and the restorative influence of sodium diethyldithiocarbamate (DTC) or deprenyl were evaluated in mice. The concentrations of dopamine (DA), 3-methoxytyramine (3-MT), 3-4-dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA), were concomitantly measured in the striatum. MPTP depressed T-cell responses. DTC restored these responses as well as the concentration of striatal DA. Deprenyl had no effect on the concentrations of DA and its metabolites, yet it modified the immune responses alike MPTP. The findings suggest a dopamine pathway could be involved in the brain-controlled immunostimulation afforded by DTC.     

TSH-suppressive treatment in differentiated thyroid cancer. A dogma under review

TSH-suppressive therapy (ST) is part of the treatment protocol for differentiated thyroid carcinoma (DTC). There is however little evidence of its clinical effectiveness. On the other side, ST is not free from side effects related to the subclinical hyperthyroidism status induced in patients for a long time period. Because of this, widespread use of ST in all patients has recently been questioned, and individualized treatment based on the characteristics of each particular case has been proposed. Action of thyroid hormones (THs) depends on their binding to specific nuclear receptors. However, a second pathway mediated by a membrane receptor located in integrin α(V)β(3) has recently been established. It has been postulated that the proliferative and angiogenic effects attributed to THs would depend on this second mechanism. It is not known whether the tumorigenic action shown in other neoplasms may have an impact on DTC. The objective of this study was to review the relationship between ST and cancer, particularly as regards tumor evolution and occurrence of second primary neoplasms. One of the future challenges in the field of DTC will be to establish the specific role of TSH and THs in malignant thyroid cells, in order to be able to define more optimized therapeutic schemes.