Effects of transcutaneous electrical nerve stimulation on physical symptoms in advanced cancer patients receiving palliative care

Transcutaneous electrical nerve stimulation (TENS) is primarily used for pain, butmight be useful for various other physical symptoms, including nausea, fatigue,dyspnea, and constipation. However, few studies have used TENS for treating thephysical symptoms of patients with advanced cancer. In this crossover trial, we assessthe effects of TENS on pain and other physical symptoms in 20 in-patients withadvanced cancer receiving palliative care. For 5-day phases between wash out periodsof 5 days, patients received TENS or non-TENS. TENS was delivered at four points: thecenter of the back for mainly nausea and dyspnea, on the back at the same dermatomallevel as the origin of the pain (100 Hz), and on both ankle joints for constipation (10Hz). The intensity of pain and the total opioid dose used during phases were recorded.Physical symptoms were evaluated using the European Organization for Research andTreatment of Cancer (EORTC) Quality of Life Questionnaire Core 15 Palliative Care(QLQ-C15-PAL). Hematological and biochemical data were recorded before and afterthe TENS phase. The average pain and total number of opioid rescue doses weresignificantly reduced by TENS. TENS tended to improve nausea and appetite loss, butnot constipation. There were no effects on hematological and biochemical parameters.Use of TENS could safely improve pain, nausea, and appetite loss in patients withadvanced cancer. Although it cannot be used as a substitute for opioids and otherpharmaceutical treatment, it may be useful to support palliative care

The Increased Expression of Integrin α6 (ITGA6) Enhances Drug Resistance in EVI1high Leukemia

Ecotropic viral integration site-1 (EVI1) is one of the candidate oncogenes for human acute myeloid leukemia (AML) with chromosomal alterations at 3q26. High EVI1 expression (EVI1high) is a risk factor for AML with poor outcome. Using DNA microarray analysis, we previously identified that integrin α6 (ITGA6) was upregulated over 10-fold in EVI1high leukemia cells. In this study, we determined whether the increased expression of ITGA6 is associated with drug-resistance and increased cell adhesion, resulting in poor prognosis. To this end, we first confirmed the expression pattern of a series of integrin genes using semi-quantitative PCR and fluorescence-activated cell sorter (FACS) analysis and determined the cell adhesion ability in EVI1high leukemia cells. We found that the adhesion ability of EVI1high leukemia cells to laminin increased with the increased expression of ITGA6 and integrin β4 (ITGB4). The introduction of small-hairpin RNA against EVI1 (shEVI1) into EVI1high leukemia cells reduced the cell adhesion ability and downregulated the expression of ITGA6 and ITGB4. In addition, the overexpression of EVI1 in EVI1low leukemia cells enhanced their cell adhesion ability and increased the expression of ITGA6 and ITGB4. In a subsequent experiment, the introduction of shRNA against ITGA6 or ITGB4 into EVI1high AML cells downregulated their cell adhesion ability; however, the EVI1high AML cells transfected with shRNA against ITGA6 could not be maintained in culture. Moreover, treating EVI1high leukemia cells with neutralizing antibodies against ITGA6 or ITGB4 resulted in an enhanced responsiveness to anti-cancer drugs and a reduction of their cell adhesion ability. The expression of ITGA6 is significantly elevated in cells from relapsed and EVI1high AML cases; therefore, ITGA6 might represent an important therapeutic target for both refractory and EVI1high AML

IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells via cereblon through downregulation of target proteins and their downstream effectors

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups. CRBN knockdown (KD) led to a loss of LEN efficacy and IKZF2-KD-induced LEN efficacy in resistant cells. DNA microarray analysis demonstrated distinct transcriptional alteration after LEN treatment between LEN-sensitive and LEN-resistant ATL cell lines. Oral treatment of LEN for ATL cell-transplanted severe combined immunodeficiency (SCID) mice also indicated clear suppressive effects on tumor growth. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL

Higher cell adhesion ability in AML cell lines with EVI1^high expression.

<p><b>A</b>. The expression of four integrin genes (ITGB1, ITGB4, ITGA4 and ITGA6), EVI1 and b-actin as a control was determined by semiquantitative RT-PCR in three different EVI1^low and EVI1^high AML cell lines and two primary AML cells lines with high EVI1 expression (PT9 and PT11). <b>B</b>. Six AML cell lines with low or high EVI1expression, as indicated in the figure, were incubated in culture medium on BSA, collagen, fibronectin, laminin or matrigel-coated plates; the percentage of the total number of incubated cells that adhered to the plates was designated as the binding activity (%). Each experiment was performed in triplicate, and the experiments were independently repeated at least three times. The data are given the as the mean ± standard error (S.E). The statistical analysis was performed using the Student's <i>t-test</i> (*<i>p</i><0.05, vs. BSA-coated plate). <b>C</b>. Six AML cell lines were incubated with the murine osteoblastic cell line MC3T3-E1, and the percentage of cells that bound to MC3T3-E1 cells was determined. Each experiment was performed in triplicate, and the experiments were independently repeated at least three times. The statistical analysis was performed using the Student's <i>t-test</i> (*<i>p</i><0.05, vs. EVI1^low cell lines).</p

The adhesion ability of EVI1^high leukemia is specifically dependent on the expression of ITGA6 and ITGB4.

<p><b>A, B, and C</b>. UCSD/AML1 cells were transiently transfected with expression vectors for shRNA against ITGA6 (shITGA6), ITGB4 (shITGB4), or ITGB1 (shITGB1), and the expression of ITGA6, ITGB4 and ITGB1 was determined using RT-PCR. UCSD/AML1 cells transfected with shRNA for firefly luciferase (shLuc) were used as a control, and the expression of b-actin was used as an internal control. <b>D, E, and F</b>. The cell adhesion ability of the cells in A, B, and C was determined through co-culture with the MC3T3-E1 cell line. The relative binding activity was calculated by comparison to the basal binding activity of control AML1/shLuc cells. <b>G</b>. The effect of neutralizing antibodies to the integrins on the cell binding activity of EVI1^high leukemia cells. Two leukemia (UCSD/AML1 and MOLM1) and two primary human AML (PT9 and PT11) cell lines were cultured on matrigel-coated plates in the presence or absence of anti-ITGA6, ITGB2, ITGB3, or ITGB4 antibodies. The relative binding activity was calculated by comparison to the basal binding activity of each cell line treated with the control isotype IgG. <b>H</b>. Two EVI1^low (K562 and U937) and three EVI1^high (UCSD/AML1, PT9 and PT11) leukemia cell lines were treated with anti-ITGA6 or ITGB4 antibodies or with the control IgG, and the binding of each cell line to the matrigel-coated plates was determined. <b>I</b>. The parental and EVI1-expressing (U937/EVI1) U937 cell lines were treated with anti-ITGA6 or control IgG, and their binding to the MC3T3-E1 cell line was determined. The relative binding activity was calculated by comparison to the basal binding activity of the parental U937 cells treated with the control isotype IgG. Each experiment was performed in triplicate, and the experiments were independently repeated at least three times. The data are given as the mean ± S.E. The statistical analysis was performed using the Student's <i>t-test</i> (*<i>p</i><0.05, vs. each control).</p

Effects of transcutaneous electrical nerve stimulation on physical symptoms in advanced cancer patients receiving palliative care

Transcutaneous electrical nerve stimulation (TENS) is primarily used for pain, but might be useful for various other physical symptoms, including nausea, fatigue, dyspnea, and constipation. However, few studies have used TENS for treating the physical symptoms of patients with advanced cancer. In this crossover trial, we assess the effects of TENS on pain and other physical symptoms in 20 in-patients with advanced cancer receiving palliative care. For 5-day phases between wash out periods of 5 days, patients received TENS or non-TENS. TENS was delivered at four points: the center of the back for mainly nausea and dyspnea, on the back at the same dermatomal level as the origin of the pain (100 Hz), and on both ankle joints for constipation (10 Hz). The intensity of pain and the total opioid dose used during phases were recorded. Physical symptoms were evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 15 Palliative Care (QLQ-C15-PAL). Hematological and biochemical data were recorded before and after the TENS phase. The average pain and total number of opioid rescue doses were significantly reduced by TENS. TENS tended to improve nausea and appetite loss, but not constipation. There were no effects on hematological and biochemical parameters. Use of TENS could safely improve pain, nausea, and appetite loss in patients with advanced cancer. Although it cannot be used as a substitute for opioids and other pharmaceutical treatment, it may be useful to support palliative care