Early Integrated Palliative Care Within a Surgical Oncology Clinic.

Importance: Advance directive (AD) designation is an important component of advance care planning (ACP) that helps align care with patient goals. However, it is underutilized in high-risk surgical patients with cancer, and multiple barriers contribute to the low AD designation rates in this population. Objective: To assess the association of early palliative care integration with changes in AD designation among patients with cancer who underwent surgery. Design, Setting, and Participants: This cohort study was a retrospective analysis of a prospectively maintained registry of adult patients who underwent elective surgery for advanced abdominal and soft tissue malignant tumors at a surgical oncology clinic in a comprehensive cancer center with expertise in regional therapeutics between June 2016 and May 2022, with a median (IQR) postoperative follow-up duration of 27 (15-43) months. Data analysis was conducted from December 2022 to April 2023. Exposure: Integration of ACP recommendations and early palliative care consultations into the surgical workflow in 2020 using electronic health records (EHR), preoperative checklists, and resident education. Main Outcomes and Measures: The primary outcomes were AD designation and documentation. Multivariable logistic regression was performed to assess factors associated with AD designation and documentation. Results: Among the 326 patients (median [IQR] age 59 [51-67] years; 189 female patients [58.0%]; 243 non-Hispanic White patients [77.9%]) who underwent surgery, 254 patients (77.9%) designated ADs. The designation rate increased from 72.0% (131 of 182 patients) before workflow integration to 85.4% (123 of 144 patients) after workflow integration in 2020 (P = .004). The AD documentation rate did not increase significantly after workflow integration in 2020 (48.9% [89 of 182] ADs documented vs 56.3% [81 of 144] ADs documented; P = .19). AD designation was associated with palliative care consultation (odds ratio [OR], 41.48; 95% CI, 9.59-179.43; P < .001), palliative-intent treatment (OR, 5.12; 95% CI, 1.32-19.89; P = .02), highest age quartile (OR, 3.79; 95% CI, 1.32-10.89; P = .01), and workflow integration (OR, 2.05; 95% CI, 1.01-4.18; P = .048). Patients who self-identified as a race or ethnicity other than non-Hispanic White were less likely to have designated ADs (OR, 0.36; 95% CI, 0.17-0.76; P = .008). AD documentation was associated with palliative care consulation (OR, 4.17; 95% CI, 2.57- 6.77; P < .001) and the highest age quartile (OR, 2.41; 95% CI, 1.21-4.79; P = .01). Conclusions and Relevance: An integrated ACP initiative was associated with increased AD designation rates among patients with advanced cancer who underwent surgery. These findings demonstrate the feasibility and importance of modifying clinical pathways, integrating EHR-based interventions, and cohabiting palliative care physicians in the surgical workflow for patients with advanced care.

Pilot Evaluation of the Online 'Chaplains-CARE' Program: Enhancing Skills for United States Military Suicide Intervention Practices and Care.

Chaplains frequently serve as first responders for United States military personnel experiencing suicidal thoughts and behaviors. The Chaplains-CARE Program, a self-paced, e-learning course grounded in suicide-focused cognitive behavioral therapy principles, was tailored for United States military chaplains to enhance their suicide intervention skills. A pilot program evaluation gathered 76 Department of Defense (DoD), Veterans Affairs (VA), and international military chaplain learners' responses. Most learners indicated that the course was helpful, easy to use, relevant, applicable, and that they were likely to recommend it to other chaplains. Based on open-ended responses, one-quarter (25.0%) of learners indicated that all content was useful, and over one-quarter (26.3%) of learners highlighted the usefulness of the self-care module. One-third (30.3%) of learners reported the usefulness of the interactive e-learning features, while others (26.3%) highlighted the usefulness of chaplains' role play demonstrations, which portrayed counseling scenarios with service members. Suggested areas of improvement include specific course adaptation for VA chaplains and further incorporation of experiential learning and spiritual care principles. The pilot findings suggest that Chaplains-CARE Online was perceived as a useful suicide intervention training for chaplains. Future training can be enhanced by providing experiential, simulation-based practice of suicide intervention skills.

Impact and Perceived Value of iGeriCare e-Learning Among Dementia Care Partners and Others: Pilot Evaluation Using the IAM4all Questionnaire.

BACKGROUND: Care partners of people living with dementia may benefit from web-based education. We developed iGeriCare, an award-winning internet-based platform with 12 multimedia e-learning lessons about dementia. OBJECTIVE: Our objective was to evaluate users' perceptions of impact. METHODS: From March 17, 2021 to May 16, 2022, data were collected upon lesson completion. We used the content-validated Information Assessment Method for all (IAM4all) for patients and the public adapted for dementia care partners. The IAM4all questionnaire assesses outcomes of web-based consumer health information. Responses were collected using SurveyMonkey, and data were analyzed using IBM SPSS Statistics (version 28). RESULTS: A total of 409 responses were collected, with 389 (95.1%) survey respondents completing the survey. Of 409 respondents, 179 (43.8%) identified as a family or friend care partner, 84 (20.5%) identified as an individual concerned they may have mild cognitive impairment or dementia, 380 (92.9%) identified the lesson as relevant or very relevant, and 403 (98.5%) understood the lesson well or very well. Over half of respondents felt they were motivated to learn more, they were taught something new, or they felt validated in what they do, while some felt reassured or felt that the lesson refreshed their memory. Of 409 respondents, 401 (98%) said they would use the information, in particular, to better understand something, discuss the information with someone else, do things differently, or do something. CONCLUSIONS: Users identified iGeriCare as relevant and beneficial and said that they would use the information. To our knowledge, this is the first time the IAM4all questionnaire has been used to assess patient and caregiver feedback on internet-based dementia education resources. A randomized controlled trial to study feasibility and impact on caregiver knowledge, self-efficacy, and burden is in progress.

Food Type and Lentil Variety Affect Satiety Responses but Not Food Intake in Healthy Adults When Lentils Are Substituted for Commonly Consumed Carbohydrates.

BACKGROUND: Lentils have potential to increase satiety and may contribute to a body weight management strategy; however, the effects on satiety of replacing common food ingredients with lentils within food products remain largely unknown. OBJECTIVE: The aim of this study was to determine the effects of replacing wheat and rice with 2 lentil varieties within muffins and chilies on satiety, test-meal food intake, and 24-h energy intake. METHODS: Healthy adults consumed muffins or chilies in which wheat or rice was substituted with green (61.8 g) or red (54 g) lentils in 2 randomized crossover studies (muffin study: n = 24, mean ± SE age: 25.4 ± 0.9 y, BMI (in kg/m2): 23.2 ± 0.5; chili study: n = 24, age: 25.7 ± 1.0 y, BMI: 23.2 ± 0.5), with ≥1-wk washout periods between study visits and studies. Subjective appetite sensations measured over 180 min were summarized with total area under the curve (AUC), food intake was measured at an ad libitum test meal, and 24-h energy intake was measured using weighed food records. Treatment effects were compared within each study using repeated-measures ANCOVA (subjective appetite sensations) and ANOVA (food intake, 24-h energy intake). RESULTS: Green, but not red, lentil chili significantly increased fullness AUC (17.5%, P = 0.02) and decreased desire to eat AUC (20.1%, P = 0.02) and prospective food consumption AUC (16.7%, P = 0.04) compared with rice chili, with no significant differences between chili treatments for test-meal food intake or 24-h energy intake. Muffin treatments did not significantly differ for any outcomes. CONCLUSIONS: Replacing rice with green, but not red lentils within chili increases satiety but does not decrease food intake, whereas replacing wheat with lentils within muffins does not increase satiety or decrease food intake in healthy adults. Further study of the role of lentil replacement in food products in body weight management is warranted. This trial was registered at clinicaltrials.gov as NCT03128684.

The Publisher's Perspective on Journal and Book Publishing.

OBJECTIVES: To provide information about the publisher's perspective on journal and book publishing. DATA SOURCES: Online publishing resources, data analytics, personal experience. CONCLUSION: Publishers provide vital tasks that support the publishing process, such as managing submissions, facilitating peer review, and manuscript editing. Publishers offer supportive and online resources, promote books and journals, and maintain archives that serve as a record of science for posterity. IMPLICATIONS FOR NURSING PRACTICE: Many nurse authors are not fully aware of the publishers' role in the publishing process, the services they provide, and the resources they offer. Knowledge and understanding of the role of the publisher can strengthen the author-publisher partnership.

Age-related variation in the cellular composition of equine bronchoalveolar lavage fluid.

BACKGROUND: Previous reports reveal variation in the cellular composition of equine bronchoalveolar lavage fluid (BALF). OBJECTIVES: The purpose of this study was to compare the profiles of BALF from horses to assess age-related differences. Serial BALF samples were collected from the same individuals over a one-year period to identify changes in individual animals as they aged. METHODS: Collection of BALF was performed on horses aged one week and one, 2, 6, and 12 months. Total nucleated cell count (TNCC), protein concentration, and cytology were assessed. Longitudinal analysis was performed and compared to healthy adults. RESULTS: Foals at one week and 6 months of age had significantly higher TNCC than adults (medians: 320/µL, 285/µL, and 90/µL, respectively); no differences in total protein were found. Foals at one month had the highest proportion of macrophages (median: 87.3%), differing significantly from both yearlings and adults (medians: 45.5% and 48.7%, respectively). Foals aged one week and one month had significantly lower proportions of lymphocytes than yearlings and adults (medians: 3.2% and 4.7% vs 43.2% and 45.8%, respectively). Eosinophil percentage was lowest in foals aged one week, one month, and 2 months (median: 0.0%) and highest in foals aged 6 months (median: 2.2%). Mast cell percentages were highest in yearlings and adults (medians: 2.2% and 3.3%, respectively) and neutrophil percentage was highest in foals aged one week (13.7%). CONCLUSIONS: Cytologic profiles of BALF from foals and adult horses differed considerably. Significant changes in TNCC and percentages of lymphocytes, macrophages, and eosinophils occurred with age.

Macrophage effector responses of horses are influenced by expression of CD154.

Reactive intermediates contribute to innate immunity by providing phagocytes with a mechanism of defense against bacteria, viruses and parasites. To better characterize the role of CD154 in the production of reactive intermediates, we cloned and expressed recombinant equine CD154 (reqCD154) in Chinese Hamster Ovary (CHO). In co-culture experiments, CHO cells ectopically expressing reqCD154 elicited superoxide production in monocyte-derived macrophages (MDM). Collectively, our results indicate that regulation of CD154 expression plays a role in innate host defenses.

Mesenchymal change and drug resistance in neuroblastoma.

BACKGROUND: Metastatic initiation has many phenotypic similarities to epithelial-to-mesenchymal transition, including loss of cell-cell adhesion, increased invasiveness, and increased cell mobility. We have previously demonstrated that drug resistance is associated with a metastatic phenotype in neuroblastoma (NB). The purpose of this project was to determine if the development of doxorubicin resistance is associated with characteristics of mesenchymal change in human NB cells. MATERIALS AND METHODS: Total RNA was isolated from wild type (WT) and doxorubicin-resistant (DoxR) human NB cell lines (SK-N-SH and SK-N-BE(2)C) and analyzed using the Illumina Human HT-12 version 4 Expression BeadChip. Differentially expressed genes (DEGs) were identified. Volcano plots and heat maps were generated. Genes of interest with a fold change in expression >1.5 and an adjusted P < 0.1 were analyzed. Immunofluorescence (IF) and Western blot analysis confirmed microarray results of interest. Matrigel invasion assay and migration wounding assays were performed. RESULTS: Volcano plots and heat maps visually demonstrated a similar pattern of DEGs in the SK-N-SH and SK-N-BE(2)C DoxR cell lines relative to their parental WT lines. Venn diagramming revealed 1594 DEGs common to both DoxR cell lines relative to their parental cell lines. Network analysis pointed to several significantly upregulated epithelial-to-mesenchymal transition pathways, through TGF-beta pathways via RhoA, PI3K, and ILK and via SMADs, as well as via notch signaling pathways. DoxR cell lines displayed a more invasive phenotype than respective WT cell lines. CONCLUSIONS: Human SK-N-SH and SK-N-BE(2)C NB cells display characteristics of mesenchymal change via multiple pathways in the transition to a drug-resistant state.

Glycolysis inhibition and its effect in doxorubicin resistance in neuroblastoma.

BACKGROUND/PURPOSE: A common trait among cancers is the increased level of glycolysis despite adequate oxygen levels to support aerobic respiration. This has been shown repeatedly in different human malignancies. Glycolysis inhibitors, especially 3-bromopyruvate, have been shown to be effective chemotherapeutic agents. The effect of glycolysis inhibition upon chemotherapy resistance is relatively unknown. METHODS: Wild-type and doxorubicin-resistant lines of neuroblastoma (SK-N-SH and SK-N-Be(2)C) were used in this study. Using an MTT assay, the IC50 of 3-BrPA was determined. Subsequently, doxorubicin-resistant cell lines were treated with 3-bromopyruvate, doxorubicin, and 3-bromopyruvate with doxorubicin. Additionally, a luminescence ATP detection assay was used to measure intracellular ATP levels, and a lactate assay was used to determine intracellular lactate levels. All experiments were repeated in hypoxic conditions. RESULTS: Treatment with 3-bromopyruvate and doxorubicin significantly decreased the mean cell viabilities at 24, 48, and 72hours in normoxic conditions. A similar response was replicated in hypoxic conditions. Treatment with 3-bromopyruvate significantly decreased intracellular ATP and lactate levels. CONCLUSION: Glycolysis inhibitors such as 3-bromopyruvate could prove to become an effective means by which chemotherapy resistance can be overcome in human neuroblastoma.

Promotoras across the border: a pilot study addressing depression in Mexican women impacted by migration.

The migration of working-aged men from Mexico to the United States fractures the family-centered support structures typical of Latin America and contributes to high levels of depression in women left behind in migratory sending communities in Mexico. Mujeres en Solidaridad Apoyandose (MESA) was developed to improve depression in women through social support in a resource poor setting. MESA is a promotora intervention that trains women in the community to lead social support groups over a five-week period. The MESA curriculum uses a combination of cognitive behavioral theory techniques, psychoeducation, and social support activities aimed at alleviating or preventing depression in women. Results from this pilot efficacy study (n = 39) show that depressed participants at baseline experienced declines in depression as measured by the Center for Epidemiologic Studies Depression Scale at follow-up. Other findings demonstrate the complexity behind addressing social support and depression for women impacted by migration in different ways.

Midkine Mediates Intercellular Crosstalk between Drug-Resistant and Drug-Sensitive Neuroblastoma Cells In Vitro and In Vivo.

Resistance to cytotoxic agents has long been known to be a major limitation in the treatment of human cancers. Although many mechanisms of drug resistance have been identified, chemotherapies targeting known mechanisms have failed to lead to effective reversal of drug resistance, suggesting that alternative mechanisms remain undiscovered. Previous work identified midkine (MK) as a novel putative survival molecule responsible for cytoprotective signaling between drug-resistant and drug-sensitive neuroblastoma, osteosarcoma and breast carcinoma cells in vitro. In the present study, we provide further in vitro and in vivo studies supporting the role of MK in neuroblastoma cytoprotection. MK overexpressing wild type neuroblastoma cells exhibit a cytoprotective effect on wild type cells when grown in a co-culture system, similar to that seen with doxorubicin resistant cells. siRNA knockdown of MK expression in doxorubicin resistant neuroblastoma and osteosarcoma cells ameliorates this protective effect. Overexpression of MK in wild type neuroblastoma cells leads to acquired drug resistance to doxorubicin and to the related drug etoposide. Mouse studies injecting various ratios of doxorubicin resistant or MK transfected cells with GFP transfected wild type cells confirm this cytoprotective effect in vivo. These findings provide additional evidence for the existence of intercellular cytoprotective signals mediated by MK which contribute to chemotherapy resistance in neuroblastoma.

The effect of vorinostat on the development of resistance to doxorubicin in neuroblastoma.

Histone deacetylase (HDAC) inhibitors, especially vorinostat, are currently under investigation as potential adjuncts in the treatment of neuroblastoma. The effect of vorinostat co-treatment on the development of resistance to other chemotherapeutic agents is unknown. In the present study, we treated two human neuroblastoma cell lines [SK-N-SH and SK-N-Be(2)C] with progressively increasing doses of doxorubicin under two conditions: with and without vorinsotat co-therapy. The resultant doxorubicin-resistant (DoxR) and vorinostat-treated doxorubicin resistant (DoxR-v) cells were equally resistant to doxorubicin despite significantly lower P-glycoprotein expression in the DoxR-v cells. Whole genome analysis was performed using the Ilumina Human HT-12 v4 Expression Beadchip to identify genes with differential expression unique to the DoxR-v cells. We uncovered a number of genes whose differential expression in the DoxR-v cells might contribute to their resistant phenotype, including hypoxia inducible factor-2. Finally, we used Gene Ontology to categorize the biological functions of the differentially expressed genes unique to the DoxR-v cells and found that genes involved in cellular metabolism were especially affected.

Mechanisms of equine infectious anemia virus escape from neutralizing antibody responses define epitope specificity.

Determining mechanisms of viral escape to particular epitopes recognized by virus-neutralizing antibody can facilitate characterization of host-neutralizing antibody responses as type- versus group-specific, and provides necessary information for vaccine development. Our study reveals that a single N-glycan located in the 5' region of the Wyoming wild-type equine infectious anemia virus (EIAV) principal neutralizing domain (PND) accounts for the differences in neutralization phenotype observed between PND variants, while variations in charged amino acids within the PND do not appear to play a key role in viral escape. Site-directed mutagenesis and peptide mapping of a conserved epitope to neutralizing antibody in the 3' region of the PND showed rapid selective pressure for acquisition of a 5' PND N-glycan responsible for defining the specificity of the neutralizing-antibody response.

Efficacy of class I and II vs class III histone deacetylase inhibitors in neuroblastoma.

BACKGROUND: Histone deacetylase (HDAC) inhibitors have shown promise in the treatment of resistant and refractory tumors including neuroblastoma. The goal of the study was to compare the efficacy of a class III HDAC inhibitor (cambinol) to a class I and II inhibitor (vorinostat). METHODS: In vitro efficacy of vorinostat and cambinol, alone or in combination with doxorubicin, was assessed by 2-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide calorimetric assay using both wild-type (WT) and doxorubicin-resistant (DoxR) SK-N-SH neuroblastoma cells. In vivo efficacy was determined using the same drug combinations in nude mice bearing xenograft implants of WT and DoxR cells on opposite flanks. RESULTS: Vorinostat and cambinol were efficacious against WT and DoxR neuroblastoma cells in vitro. In WT cells, the potency of the doxorubicin itself overshadowed any effect of cotherapy with vorinostat or cambinol. The effect of vorinostat and/or cambinol on the DoxR cells was constant across progressively increasing doses of doxorubicin. In the in vivo model, the efficacy of doxorubicin itself (88% reduction in tumor volume) again overshadowed any effect of cotreatment with vorinostat or cambinol on the WT tumors. However, in the DoxR tumors, doxorubicin alone had no efficacy, but cotreatment with either cambinol or vorinostat suppressed tumor growth (70% and 91% reduction in tumor volume, respectively). CONCLUSIONS: Both the class III HDAC inhibitor cambinol and the class I/II HDAC inhibitor vorinostat have efficacy against SK-N-SH neuroblastoma cells, including those resistant to doxorubicin.

Myxoid variant of anaplastic large cell lymphoma involving the skin: a case report.

We report the case of a 62-year-old white male who presented with a 2.6-cm ulcerating mass on the skin of the left buttock and ipsilateral inguinal lymphadenopathy. Microscopic sections of the skin lesion showed a nodular and plaque-like growth pattern of a mixed cellular infiltrate throughout the dermis and subcutaneous tissue with prominent myxoid change. There was a dominant population of medium-sized mitotically active atypical cells that expressed CD30, CD4 and EMA. These atypical cells were mixed with eosinophils, neutrophils, mature lymphocytes and histiocytes. Tissue from the inguinal lymphadenopathy showed similar pathologic features, although no residual lymph node tissue was present. A diagnosis of secondary anaplastic large cell lymphoma, myxoid variant, with skin and lymph node/perinodal soft tissue involvement was rendered at the time of complete excision of the buttock mass. The patient received five cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy with complete resolution of lymphadenopathy and no residual cutaneous disease. He was disease-free by PET/CT scan and physical examination at 16 months after chemotherapy. We present this case to highlight the histopathologic and immunophenotypic features of this entity with a discussion of the differential diagnosis and a review of the literature.

Alloimmune neonatal neutropenia and neonatal isoerythrolysis in a Thoroughbred colt.

A 3-day-old Thoroughbred colt was originally presented for treatment of neonatal isoerythrolysis, which was treated with a blood transfusion. However, persistent neutropenia was observed despite the absence of detectable infection. Subsequently, a granulocyte agglutination test was performed by incubating the colt's neutrophils with the mare's serum; results were positive, leading to a clinical diagnosis of alloimmune neonatal neutropenia. The diagnosis was further supported via flow cytometric analysis. The colt was hospitalized and treated prophylactically with antimicrobials and 4 separate doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF; 1.4-3.5 µg/kg, subcutaneously) in attempts to maintain the neutrophil count within reference intervals over a 4-week period. The colt's neutrophil count increased after administration of rhG-CSF and eventually stabilized within reference intervals by day 20. The colt maintained normal neutrophil counts after discharge and was reportedly healthy at 6 months of age. Alloimmune neonatal neutropenia should be considered in foals with persistent neutropenia in the absence of infection. Alloimmune neonatal neutropenia can be treated with prophylactic antimicrobials combined with rhG-CSF with a favorable outcome.

Synthesis and In vitro activity of ROMP-based polymer nanoparticles.

A new type of polymer nanoparticle (PNP) containing a high density of covalently linked doxorubicin, attached via a non-cleavable amine linkage (amine-linked Dox-PNP) was prepared. Together with a previously reported cleavable carbamate-linked Dox-PNP, this new amine-linked Dox-PNP was subsequently evaluated against free doxorubicin for its cytotoxicity and inhibitory effects on SKNSH wild-type and SKrDOX6 doxorubicin-resistant human neuroblastoma cell lines. Analogous cholesterol-containing PNPs (Chol-PNPs) and indomethacin-containing PNPs (IND-PNPs) were also synthesized and used as the non-cytotoxic controls. While neither cell line was affected by Chol-PNPs or IND-PNPs, SKrDOX6 doxorubicin-resistant cells exhibited similar cytotoxic responses to free doxorubicin and both amine- and carbamate-linked Dox-PNPs, suggesting that doxorubicin or the doxorubicin-containing polymer must be the active agent in the latter case. SKNSH wild-type cells also responded to both Dox-PNPs, albeit at a higher apparent concentration than free doxorubicin alone. The growth of SKNSH wild-type cells was significantly inhibited upon incubation with carbamate-linked Dox-PNPs, as with free doxorubicin, over a 7-day period. In comparison to free doxorubicin, carbamate-linked Dox-PNPs produced a longer (72-h) period of initial inhibition in SKrDOX6 doxorubicin-resistant cells.

The sounds of silence: language, cognition, and anxiety in selective mutism.

OBJECTIVES: To determine whether oral language, working memory, and social anxiety differentiate children with selective mutism (SM), children with anxiety disorders (ANX), and normal controls (NCs) and explore predictors of mutism severity. METHOD: Children ages 6 to 10 years with SM (n = 44) were compared with children with ANX (n = 28) and NCs (n = 19) of similar age on standardized measures of language, nonverbal working memory, and social anxiety. Variables correlating with mutism severity were entered in stepwise regressions to determine predictors of mute behavior in SM. RESULTS: Children with SM scored significantly lower on standardized language measures than children with ANX and NCs and showed greater visual memory deficits and social anxiety relative to these two groups. Age and receptive grammar ability predicted less severe mutism, whereas social anxiety predicted more severe mutism. These factors accounted for 38% of the variance in mutism severity. CONCLUSIONS: Social anxiety and language deficits are evident in SM, may predict mutism severity, and should be evaluated in clinical assessment. Replication is indicated, as are further studies of cognition and of intervention in SM, using large, diverse samples.

Identification of midkine as a mediator for intercellular transfer of drug resistance.

Resistance to cytotoxic agents is a major limitation for their clinical use to treat human cancers. Tumors become resistant to chemotherapy when a subset of cells undergoes molecular changes leading to overexpression of drug transport proteins, alterations in drug-target interactions or reduced ability to commit apoptosis. However, such changes may not be sufficient to explain why both resistant and nonresistant cells survive drug's action in tumors that ultimately become drug resistant. We hypothesized that, in such tumors, a cytoprotective relationship may exist between drug-resistant and neighboring drug-sensitive cells. The present study addresses the possibility that drug-resistant cells secrete in their culture medium factors able to protect sensitive cells from drug toxicity. A survival molecule, midkine, was identified by cDNA array to be expressed only in drug-resistant cells. Midkine-enriched fractions obtained by affinity chromatography exert a significant cytoprotective effect against doxorubicin in the wild-type drug-sensitive cells. Moreover, transfection of these cells with the midkine gene caused a decreased response to doxorubicin. The underlying mechanism of this cytoprotection appeared to imply activation of the Akt pathway and inhibition of drug-induced proliferation arrest as well as apoptotic cell death. These findings provide evidence for the existence of intercellular cytoprotective signals such as the one mediated by midkine, originating from cells with acquired drug resistance to protect neighboring drug-sensitive cells and thus contribute to development of resistance to chemotherapy.