A scoping review of academic and grey literature on migrant health research conducted in Scotland.

BACKGROUND: Migration to Scotland has increased since 2002 with an increase in European residents and participation in the Asylum dispersal scheme. Scotland has become more ethnically diverse, and 10% of the current population were born abroad. Migration and ethnicity are determinants of health, and information on the health status of migrants to Scotland and their access to and barriers to care facilitates the planning and delivery of equitable health services. This study aimed to scope existing peer-reviewed research and grey literature to identify gaps in evidence regarding the health of migrants in Scotland. METHODS: A scoping review on the health of migrants in Scotland was carried out for dates January 2002 to March 2023, inclusive of peer-reviewed journals and grey literature. CINAHL/ Web of Science/SocIndex and Medline databases were systematically searched along with government and third-sector websites. The searches identified 2166 journal articles and 170 grey literature documents for screening. Included articles were categorised according to the World Health Organisation's 2016 Strategy and Action Plan for Refugee and Migrant Health in the European region. This approach builds on a previously published literature review on Migrant Health in the Republic of Ireland. RESULTS: Seventy-one peer reviewed journal articles and 29 grey literature documents were included in the review. 66% were carried out from 2013 onwards and the majority focused on asylum seekers or unspecified migrant groups. Most research identified was on the World Health Organisation's strategic areas of right to health of refugees, social determinants of health and public health planning and strengthening health systems. There were fewer studies on the strategic areas of frameworks for collaborative action, preventing communicable disease, preventing non-communicable disease, health screening and assessment and improving health information and communication. CONCLUSION: While research on migrant health in Scotland has increased in recent years significant gaps remain. Future priorities should include studies of undocumented migrants, migrant workers, and additional research is required on the issue of improving health information and communication.

The Impact of Health Equity-Informed Eligibility Criteria to Increase the Delivery of Pharmacist-Delivered Comprehensive Medication Management Services for Patients with High Blood Pressure.

OBJECTIVE: Evaluate a cardiovascular care intervention intended to increase access to comprehensive medication management (CMM) pharmacy care and improve vascular health goals among socially disadvantaged patients. DESIGN: Retrospective electronic health records-based evaluation. SETTING: Thirteen health care clinics serving socially vulnerable neighborhoods within a large health system. PARTICIPANTS: Hypertensive and hyperlipidemic adult patients. INTERVENTION: CMM pharmacists increased recruitment among patients who met clinical criteria in clinics serving more diverse and socially vulnerable communities. CMM pharmacists partnered with patients to work toward meeting health goals through medication management and lifestyle modification. MAIN OUTCOME MEASURES: Changes in the engagement of socially disadvantaged patients between preintervention and intervention time periods; vascular health goals (ie, controlled blood pressure, appropriate statin and aspirin therapies, and tobacco nonuse); and the use of health system resources by CMM care group. RESULTS: The intervention indicated an overall shift in sociodemographics among patients receiving CMM care (fewer non-Hispanic Whites: N = 1988, 55.81% vs N = 2264, 59.97%, P < .001; greater place-based social vulnerability: N = 1354, 38.01% vs N = 1309, 34.68%, P = .03; more patients requiring interpreters: N = 776, 21.79% vs N = 698, 18.49%, P < .001) compared to the preintervention period. Among patients meeting intervention criteria, those who partnered with CMM pharmacists (N = 439) were more likely to connect with system resources (social work: N = 47, 10.71% vs 163, 3.74%, P < .001; medical specialists: N = 249, 56.72% vs N = 1989, 45.66%; P < .001) compared to those without CMM care (N = 4356). Intervention patients who partnered with CMM pharmacists were also more likely to meet blood pressure (N = 357, 81.32% vs N = 3317, 76.15%, P < .001) and statin goals (N = 397, 90.43% vs N = 3509, 80.56%, P < .001) compared to non-CMM patients. CONCLUSIONS: The demographics of patients receiving CMM became more diverse with the intervention, indicating improved access to CMM pharmacists. Cultivating relationships among patients with greater social disadvantage and cardiovascular disease and CMM pharmacists may improve health outcomes and connect patients to essential resources, thus potentially improving long-term cardiovascular outcomes.

Mechanisms of impact of alcohol availability interventions from the perspective of 63 diverse alcohol licensing stakeholders: a qualitative interview study.

Aims: Interventions restricting temporal and spatial availability of alcohol are associated with reduced harm, but the pathways by which specific interventions have impact are poorly understood. We examined mechanisms of impact from the perspective of diverse licensing stakeholders. Methods: Fifty-three in-depth interviews were conducted with licensing stakeholders (from public health teams [PHTs], police, local authority licensing teams and lawyers, and alcohol premises licensing committees) from 20 local government areas. Interviewees were recruited as part of the Exploring the impact of alcohol licensing in England and Scotland (ExILEnS) study. Data were analyzed thematically and preliminary themes/subthemes were discussed during online groups with a different sample of public health and licensing professionals (n = 10). Findings: Most interviewees struggled to articulate how availability interventions might lead to changes in alcohol consumption or harms. Five overarching mechanisms were identified: access, visibility, premises and area-level norms, affordability, and management of the night-time economy, with specific pathways identified for certain subgroups/premises types. The mechanisms by which alcohol availability interventions may impact on alcohol consumption and harms are diverse, but were poorly understood. Conclusions: These findings will inform licensing and availability policy and advocacy, highlighting the need for further scrutiny of the evidence underpinning identified mechanisms, and primary research to address knowledge gaps.

'Give us the real tools to do our jobs': views of UK stakeholders on the role of a public health objective for alcohol licensing.

OBJECTIVES: This study ascertains the views of UK stakeholders on the actual, and possible, impact of a public health licensing objective in their day-to-day work. STUDY DESIGN AND METHODS: Twenty-eight interviews were conducted with members of public health teams who were actively engaged in alcohol licensing in their local area between 2017 and 2019. Six teams were based in Scotland (where there is a public health licensing objective) and 14 in England (where there is no similar objective). RESULTS: Scottish participants reported that while challenges remained in applying the public health licensing objective, progress had been made and the objective was beneficial to their work. Participants in England felt that an objective would increase the legitimacy, value and impact of their contributions. In both Scotland and England, constructive relationships between PHTs, licensing authorities and other key stakeholders were developing suggesting that PHTs could have a sustainable and positive role in licensing. CONCLUSIONS: In many Scottish areas, the alcohol licensing system is evolving to take constructive account of its public health objective. In England, PHTs that have invested resources in engaging in this area have demonstrated an ability to work effectively within licensing systems. Strong support for the adoption of a public health licensing objective among these PHTs adds weights to calls for the UK Government to reconsider its previous decision not to introduce such an objective.

Dental public health in action: The covid-19 restrictions on dentistry in England and their impact on access to dental care for high-risk patient groups in the North-East and North Cumbria.

The Covid-19 pandemic has significantly impacted dental practices with the initial response being a complete suspension of face to face care unless designated as an urgent care centre. Even with subsequent easing of restrictions, a significant change to the delivery of dental care is continuing to restrict patient access. The introduction of new Standard Operating Procedures, with a benchmark fallow time of 15 to 30 minutes after aerosol generating procedures, has also reduced capacity levels within dental practices. Triaging systems have been implemented within practices to ensure those with the highest oral health care needs are prioritised for face to face care. Altered patient attendance, due to the Covid-19 restrictions placed upon dental care, may also be compounded by patients avoiding dental care due to personal perceptions of risks associated with Covid-19 or due to a desire not to overburden health systems. With the additional Covid-19 restrictions in place the access to dental care for vulnerable populations may have been even further impacted, there is therefore a concern that the restrictions may have exacerbated inequalities in oral health for these groups. Public health competencies illustrated: Developing and monitoring the quality of dental services, Dental Public Health Intelligence, and Policy and Strategy Development are illustrated within this project.

'They only smoke in the house when I'm not in': understanding the limited effectiveness of a smoke-free homes intervention.

BACKGROUND: Children's second-hand smoke (SHS) exposure in the home is highest in socio-economically disadvantaged areas. Personalized household air-quality measurements can promote changes in smoking that reduce SHS exposure. The 'First Steps 2 Smoke-free' (FS2SF) intervention is the first to trial this approach delivered as part of health professionals' routine work. This paper reports the findings of qualitative interviews with participants that explored their experiences of the intervention and why outcomes varied. METHODS: 120 women were recruited from the NHS First Steps Programme, which supports disadvantaged mothers. They received either personalized feedback on their home air quality and advice on reducing SHS or standard SHS advice. Qualitative interviews with 15 mothers were analyzed thematically using the Capability, Opportunity, Motivation, Behaviour (COM-B) model. RESULTS: The intervention increased women's capability to change home-smoking behaviour, through increasing awareness and salience of SHS risks to their children, and motivation to act. However, taking effective action was constrained by their limited social and environmental opportunities, including others' smoking in the home. CONCLUSIONS: The FS2SF intervention was ineffective as it was unable to fully address the precarious, complex life circumstances that make creating a smoke-free home particularly difficult for women experiencing intersecting dimensions of disadvantage.

Assessing the function of homologous recombination DNA repair in malignant pleural effusion (MPE) samples.

BACKGROUND: Patients with malignant pleural effusions (MPEs) generally have advanced disease with poor survival and few therapeutic options. Cells within MPEs may be used to stratify patients for targeted therapy. Targeted therapy with poly(ADP ribose) polymerase inhibitors (PARPi) depends on identifying homologous recombination DNA repair (HRR)-defective cancer cells. We aimed to determine the feasibility of assaying HRR status in MPE cells. METHODS: A total of 15 MPE samples were collected from consenting patients with non-small-cell lung cancer (NSCLC), mesothelioma and ovarian and breast cancer. Primary cultures were confirmed as epithelial by pancytokeratin, and HRR status was determined by the detection of γH2AX and RAD51 foci following a 24-h exposure to rucaparib, by immunofluorescence microscopy. Massively parallel next-generation sequencing of DNA repair genes was performed on cultured MPE cells. RESULTS: From 15 MPE samples, 13 cultures were successfully established, with HRR function successfully determined in 12 cultures. Four samples - three NSCLC and one mesothelioma - were HRR defective and eight samples - one NSCLC, one mesothelioma, one sarcomatoid, one breast and four ovarian cancers - were HRR functional. No mutations in DNA repair genes were associated with HRR status, but there was probable loss of heterozygosity of FANCG, RPA1 and PARP1. CONCLUSIONS: HRR function can be successfully detected in MPE cells demonstrating the potential to stratify patients for targeted therapy with PARPi.

Physiological sex steroid replacement in premature ovarian failure: randomized crossover trial of effect on uterine volume, endometrial thickness and blood flow, compared with a standard regimen.

BACKGROUND: Premature ovarian failure (POF) is currently managed by non-physiological sex steroid regimens which are inadequate at optimizing uterine characteristics. Previous short-term studies have demonstrated some benefits of a sex steroid replacement (SSR) regimen devised to replicate the physiological cycle. This study aimed to directly compare the effects of longer-term administration of physiological SSR (pSSR) and standard SSR (sSSR) regimens on the uterine volume, blood flow and endometrial thickness (ET) in women with POF. METHODS: In a controlled crossover trial, 34 women with POF were randomized to receive 12 months of 4-week cycles of transdermal estradiol and vaginal progesterone (pSSR) followed by 12 months of 4-week cycles of oral ethinylestradiol and norethisterone (sSSR), or vice versa. Each treatment period was preceded by a 2-month washout period. At 0, 3, 6 and 12 months of each treatment period, transvaginal ultrasound examined the uterine volume and ET, as primary end-points, and uterine artery resistance (UARI) and pulsatility indices (UAPI), as secondary end-points. Serum estradiol, progesterone and gonadotrophins were also measured. RESULTS: Of the 29 women eligible for the uterine analysis, 17 completed the entire study protocol, but 25 women contributed data to statistical analysis of treatment effect. There was a greater estimated mean ET with the use of pSSR (4.8 mm) compared to that with standard therapy (3.0 mm), with an estimated difference of 1.8 mm [95% confidence interval (CI), 0.7 to 2.8, P=0.002]. The estimated mean uterine volume was also greater during physiological treatment (24.8 cm(3)) than during standard treatment (20.6 cm(3)), but the estimated difference of 4.2 cm(3) (95% CI -0.4 to 8.7) was not statitsically significant, P=0.070. The small differences between the two treatments in the mean UARI and mean UAPI were not statistically significant. The estimated treatment differences were fairly constant across the treatment periods, suggesting that prolonged treatment does not increase response. CONCLUSIONS: pSSR has a greater beneficial effect upon ET in women with POF in comparison with standard therapy. A similar trend was seen for uterine volume. Further studies are required to optimize treatment and to assess pregnancy rate and outcome. Trial Registration www.ClinicalTrials.gov, NCR00732693.

Functional conservation of the malaria vaccine antigen MSP-119across distantly related Plasmodium species.

The C-terminal region of Plasmodium falciparum merozoite surface protein 1 (MSP-119) is at present a leading malaria vaccine candidate. Antibodies against the epidermal growth factor-like domains of MSP-1 19are associated with immunity to P. falciparum and active immunization with recombinant forms of the molecule protect against malaria challenge in various experimental systems. These findings, with the knowledge that epidermal growth factor-like domains in other molecules have essential binding functions, indicate the importance of this protein in merozoite invasion of red blood cells. Despite extensive molecular epidemiological investigations, only limited sequence polymorphism has been identified in P. falciparum MSP-119 (refs. 9-11). This indicates its sequence is functionally constrained, and is used in support of the use of MSP-119 as a vaccine. Here, we have successfully complemented the function of most of P. falciparum MSP-119 with the corresponding but highly divergent sequence from the rodent parasite P. chabaudi. The results indicate that the role of MSP-119 in red blood cell invasion is conserved across distantly related Plasmodium species and show that the sequence of P. falciparum MSP-119 is not constrained by function.

Antibodies against merozoite surface protein (MSP)-1(19) are a major component of the invasion-inhibitory response in individuals immune to malaria.

Antibodies that bind to antigens expressed on the merozoite form of the malaria parasite can inhibit parasite growth by preventing merozoite invasion of red blood cells. Inhibitory antibodies are found in the sera of malaria-immune individuals, however, the specificity of those that are important to this process is not known. In this paper, we have used allelic replacement to construct a Plasmodium falciparum parasite line that expresses the complete COOH-terminal fragment of merozoite surface protein (MSP)-1(19) from the divergent rodent malaria P. chabaudi. By comparing this transfected line with parental parasites that differ only in MSP-1(19), we show that antibodies specific for this domain are a major component of the inhibitory response in P. falciparum-immune humans and P. chabaudi-immune mice. In some individual human sera, MSP-1(19) antibodies dominated the inhibitory activity. The finding that antibodies to a small region of a single protein play a major role in this process has important implications for malaria immunity and is strongly supportive of further understanding and development of MSP-1(19)-based vaccines.

Chick embryonic skin as a rapid organ culture assay for cellular neoplasia.

We used chick embryonic skin (CES) in organ culture to assess the neoplastic potential of a variety of cultured human and nonhuman cell lines. Cells derived from cancer tissues grew in CES and formed tumors in nude mice while cells derived from normal tissues grew in neither system. The CES proved to be more sensitive than the nude mouse when used to assay SV40 transformed human cells; each of four such lines grew in CES while only one of the four lines grew and formed tumors in nude mice. In addition, the patterns of invasion by inoculated cells can be easily studied in the CES. These results suggest that CES in organ culture offers an inexpensive, rapid, and reliable alternative to the nude mouse as a tumorigenicity test.

Patient safety ward round checklist via an electronic app: implications for harm prevention.

INTRODUCTION: Patient safety is a value at the core of modern healthcare. Though awareness in the medical community is growing, implementing systematic approaches similar to those used in other high reliability industries is proving difficult. The aim of this research was twofold, to establish a baseline for patient safety practices on routine ward rounds and to test the feasibility of implementing an electronic patient safety checklist application. METHODS: Two research teams were formed; one auditing a medical team to establish a procedural baseline of "usual care" practice and an intervention team concurrently was enforcing the implementation of the checklist. The checklist was comprised of eight standard clinical practice items. The program was conducted over a 2-week period and 1 month later, a retrospective analysis of patient charts was conducted using a global trigger tool to determine variance between the experimental groups. Finally, feedback from the physician participants was considered. RESULTS: The results demonstrated a statistically significant difference on five variables of a total of 16. The auditing team observed low adherence to patient identification (0.0%), hand decontamination (5.5%), and presence of nurse on ward rounds (6.8%). Physician feedback was generally positive. CONCLUSIONS: The baseline audit demonstrated significant practice bias on daily ward rounds which tended to omit several key-proven patient safety practices such as prompting hand decontamination and obtaining up to date reports from nursing staff. Results of the intervention arm demonstrate the feasibility of using the Checklist App on daily ward rounds.

Enhancement of the therapeutic index: from nonmyeloablative and myeloablative toward pretargeted radioimmunotherapy for metastatic prostate cancer.

PURPOSE: New strategies that target selected molecular characteristics and result in an effective therapeutic index are needed for metastatic, hormone-refractory prostate cancer. EXPERIMENTAL DESIGN: A series of preclinical and clinical studies were designed to increase the therapeutic index of targeted radiation therapy for prostate cancer. (111)In/90Y-monoclonal antibody (mAb), m170, which targets aberrant sugars on abnormal MUC1, was evaluated in androgen-independent prostate cancer patients to determine the maximum tolerated dose and efficacy of nonmyeloablative radioimmunotherapy and myeloablative combined modality radioimmunotherapy with paclitaxel. To enhance the tumor to liver therapeutic index, a cathepsin degradable mAb linkage ((111)In/90Y-peptide-m170) was used in the myeloablative combined modality radioimmunotherapy protocol. For tumor to marrow therapeutic index improvement in future studies, anti-MUC1 scFvs modules were developed for pretargeted radioimmunotherapy. Anti-MUC1 and anti-DOTA scFvs were conjugated to polyethylene glycol scaffolds tested on DU145 prostate cancer cells and prostate tissue arrays, along with mAbs against MUC1 epitopes. RESULTS: The nonmyeloablative maximum tolerated dose of 90Y-m170 was 0.74 GBq/m2 for patients with not more than 10% axial skeleton involvement. Metastatic prostate cancer was targeted in all 17 patients; mean radiation dose was 10.5 Gy/GBq and pain response occurred in 7 of 13 patients reporting pain. Myeloablative combined modality radioimmunotherapy with 0.4 GBq/m2 of 90Y-peptide-m170 and paclitaxel showed therapeutic effects in 4 of 6 patients and 30% less radiation to the liver per unit of activity. Neutropenia was dose limiting without marrow support and patient eligibility was a major limitation to dose escalation. Hypoglycosylated MUC1 epitopes were shown to be abundant in prostate cancer and to increase with disease grade. Anti-MUC1 scFvs binding to prostate cancer tissue and live cells were developed into di-scFv binding modules. CONCLUSIONS: The therapeutic index enhancement for prostate radioimmunotherapy was achieved in clinical studies by the addition of cathepsin cleavable linkers to 90Y-conjugated mAbs and the use of paclitaxel. However, the need for marrow support in myeloablative combined modality radioimmunotherapy restricted eligible patients. Therefore, modular pretargeted radioimmunotherapy, aiming at improving the tumor to marrow therapeutic index, is being developed.

An alteration in concatameric structure is associated with efficient segregation of plasmids in transfected Plasmodium falciparum parasites.

Transfection of the human malaria parasite Plasmodium falciparum is currently performed with circularised plasmids that are maintained episomally in parasites under drug selection but which are rapidly lost when selection pressure is removed. In this paper, we show that in instances where gene targeting is not favoured, transfected plasmids can change to stably replicating forms (SRFs) that are maintained episomally in the absence of drug selection. SRF DNA is a large concatamer of the parental plasmid comprising at least nine plasmids arranged in a head-to-tail array. We show as well that the original unstable replicating forms (URFs) are also present as head-to-tail concatamers, but only comprise three plasmids. Limited digestion and gamma irradiation experiments revealed that while URF concatamers are primarily circular, as expected, SRF concatamers form a more complex structure that includes extensive single-stranded DNA. No evidence of sequence rearrangement or additional sequence was detected in SRF DNA, including in transient replication experiments designed to select for more efficiently replicating plasmids. Surprisingly, these experiments revealed that the bacterial plasmid alone can replicate in parasites. Together, these results imply that transfected plasmids are required to form head-to-tail concatamers to be maintained in parasites and implicate both rolling-circle and recombination-dependent mechanisms in their replication.

Effect of dioctyl sodium sulfosuccinate feeding on rat colorectal 1,2-dimethylhydrazine carcinogenesis.

The 1,2-dimethylhydrazine (DMH) rodent model for colorectal carcinogenesis was used to explore the effect of dietary dioctyl sodium sulfosuccinate (DSS) on carcinogenesis. Inbred male F344 rats were divided into two groups of 84 each and fed the following diets: ground chow and 5% corn oil (control group) and ground chow, 5% corn oil, and 1% DSS (experimental group). All rats received high-dose DMH base, 20 mg/kg/week sc for 20 weeks. Twenty rats per group were killed after 3, 4, 5, and 6 months. Duodenum, small intestine, colon, and rectum were dissected out. Each tumor was measured for size and location and evaluated histologically. The percentage of rats bearing tumors in the control and experimental groups did not differ significantly. In each rat there were fewer gastrointestinal tumors in the DSS-fed group of all histologic types combined, at all organ sites, at 5 and 6 months. This difference between the control and DSS-fed rats reached the level of statistical significance for tumors of the duodenum, colon, and rectum and for total gastrointestinal tumors at the 5th month.

Effect of BCG immunotherapy on N-nitroso-N-methylurea-induced carcinogenesis of guinea pig colon.

A total of 480 guinea pigs each received twice weekly intrarectal instillations of 1 mg N-nitroso-N-methylurea (NMU) during 14-35 weeks (total dose NMU, 28-70 mg) to induce colon neoplasms. At 24, 28, or 35 weeks after the start of NMU instillation, the distal colon was exposed by a ventral laparotomy and suspected neoplastic lesions were treated by one of four methods: A, intratumoral instillation of an emulsion of killed BCG cell walls attached to oil droplets; B, intratumoral instillation of a control emulsion of killed BCG cell walls in an aqueous phase rather than lipid phase; C, surgical excision of the colon lesion with formation of a ventral diverting colostomy; or D, sham operation (no treatment). All guinea pigs were allowed to recover from surgery and were then observed for a period of 1 year for the study of the effects of these treatments on NMU-induced colon neoplasms. Colon neoplasms were produced in 76% of all sham-operated control guinea pigs, and the frequency of such neoplasms was dependent on the total dose of NMU. Most neoplasms were adenocarcinomas with invasion of the bowel wall but only approximately 5% of them metastasized. Treatment with BCG failed to alter the course of NMU-induced colon carcinogenesis, as determined by the frequency of colon neoplasia, the number, the gross, or microscopic characteristics of colon neoplasms, or the rate of survival.

Antitumor immunity induced by hybrid murine tumor cells: requirements for optimal immunization.

Hybrid tumor cells have been evaluated for their ability to induce specific antitumor immunity in inbred female C3H/He mice challenged with the syngeneic BA tumor. Hybrid cells were produced by fusion of BA cells with a BALB/c renal adenocarcinoma, which is hypoxanthine phosphoribosyl transferase-deficient and grows well in culture. Corynebacterium parvum was evaluated as an adjuvant for BA and hybrid cells. The BA tumor was shown to be poorly immunogenic, and four weekly injections of BA cells alone or C. parvum alone did not confer significant immunity. When BA cells and C. parvum were mixed, survival time was prolonged and most mice remained tumor-free. Hybrid cell lines derived from the BA tumor were produced in culture in unlimited quantities and were successfully used as immunogens. The addition of C. parvum to hybrids gave a significant incremental increase in survival when compared to the survival resulting from immunization by hybrids without adjuvant. When hybrids without adjuvant were used, several weekly injections were required for effective immunization. Irradiated and unirradiated hybrids were compared, and it was found that irradiation did not diminish hybrid immunogenicity. The potential problems and advantages of this concept of therapy are discussed.

Establishment and biological properties of a guinea pig colonic adenocarcinoma cell line induced by N-methyl-N-nitrosourea.

A colonic adenocarcinoma cell line, designated GPC-16, was established in culture from tissue removed from an outbred guinea pig which received 56 mg of N-methyl-N-nitrosourea intrarectally over a 28-week period. the GPC-16 has been maintained for more than 30 in vitro passages and was tumorigenic in both the autochthonous host and nude mice. The cells were aneuploid with a wide range in chromosome number (54 to 172) in a bimodal distribution. The cells grew in vitro as a tight monolayer and demonstrated numerous desmosomes by electron microscopy. In vitro-passaged cells had a doubling time of 36 hr and a 5.1% plating efficiency in agar.

In vivo enhancement of antitumor immunity by interleukin 2-rich lymphokines.

The ability of interleukin 2 (IL-2) to enhance in vivo antitumor immunity has been evaluated in the line 1 alveolar cell carcinoma (L1) model of BALB/c mice. A crude supernatant from phorbol myristate acetate exposed EL-4 cells rich in IL-2 plus other lymphokines (EL-4 IL-2), a concanavalin A-induced supernatant from murine splenocytes (Con A IL-2), and recombinant IL-2 (rIL-2) provided by Biogen were tested. Mice were immunized with a cloned population of L1 cells (10(6) irradiated L1 cells given s.c. in the left inguinal region) followed by s.c. injections of EL-4 IL-2, Con A IL-2, or rIL-2 given to the same site. Two immunizations of L1 cells each followed by IL-2 administration were given prior to challenge with live L1 cells s.c. on the right chest wall. Mice receiving EL-4 IL-2 survived significantly longer than those receiving L1 cells only. Daily administration of EL-4 IL-2 for 7 days after the last L1 immunization was significantly better than 3 days (P less than 0.01) which in turn was significantly better than 1 day (P less than 0.05). Among the doses tested (normalized in vitro to the Biologic Response Modifiers Program IL-2 standard) 404 units of IL-2/injection was optimal. The EL-4 IL-2 had to be injected adjacent to the site of L1 cells; s.c. injection at a distant site or i.p. was not effective. When rIL-2 or Con A IL-2 was substituted for EL-4 IL-2, survival was not prolonged; however, if Con A IL-2 (low IL-2 levels) was supplemented with rIL-2 to 404 units of IL-2, it augmented immunity as well as 404 units of EL-4 IL-2. The data suggest that IL-2 is not the only lymphokine active in augmenting antitumor immunity induced by L1 cells. Some preliminary experiments indicate that a multilymphokine approach may have potential clinical relevance.

Antitumor immunity induced by hybrid tumor cells: comparison between hybrids and the parental tumor.

The ability of hybrid tumor cells to induce antitumor immunity has been evaluated in the line 1 alveolar cell carcinoma (L1) model of BALB/c mice. Hybrid tumor cells were produced by fusing freshly dissociated L1 cells isolated from in vivo tumors with the hypoxanthine:aminopterin:thymidine-sensitive cell line, GM 347, derived from C3H mice. Each hybrid was characterized by DNA content and expression of H-2 antigens using a fluorescence-activated cell sorter. Irradiated L1 cells in the presence or absence of Corynebacterium parvum were capable of immunizing BALB/c mice against a challenge of live L1 cells, provided the challenge dose was small (50% lethal dose was between 6 X 10(4) and 1.2 X 10(5) L1 cells). Testing of five hybrid clones and 1 uncloned hybrid line for their immunizing ability demonstrated a range in immunizing ability with none showing a statistically significant improvement in survival (p less than 0.0018) when compared to untreated controls. However, one hybrid clone, MoHb-L1-C2, was selected in which the survival of mice immunized with it compared to controls had a p value of 0.0255. A tumor (labeled L1/A) which grew in one of the mice immunized with this clone was removed and hybridized with GM 347 to yield a second set of hybrids. Both this variant of L1 cells and a hybrid clone made from it (MoHb-L1A-C18) were capable of immunizing mice against a challenge of live L1/A (p values of 0.0000 and 0.0028, respectively, when compared to controls). However, L1 cells were not able to immunize effectively against L1/A, and MoHb-L1A-C18 did not immunize against L1. This suggests that L1/A is a subpopulation of L1 cells with a different antigenic composition. The limited success of MoHb-L1A-C18 against L1/A is thought to be due to the narrower range of antigenic specificities in L1/A and the ability of MoHb-L1A-C18 to represent an important antigenic subpopulation of L1/A.