Alimentation infantile et changements climatiques : une opportunité prometteuse.

The method of infant feeding has consequences for the production of greenhouse gases (GHG) as well as for the risks to infants posed by climate change. Breastfeeding can reduce the carbon footprint associated with the use of commercial infant formula by nearly 50% while reducing its water footprint and waste. It is also an excellent way of coping with emergencies associated with climate change, such as water shortages, since breastfed children are better protected than those fed with formula. To ensure that the protection offered by breastfeeding can be realized, we present elements that can help decision-makers seize a promising opportunity: improve infant feeding support for women and families.

RéSUMé: Le mode d'alimentation infantile a des répercussions sur les émissions de gaz à effets de serre (GES) de même que sur les risques que posent les changements climatiques pour les nourrissons. L'allaitement peut réduire de près de 50 % l'empreinte carbone associée à l'utilisation des préparations commerciales pour nourrissons (PCN) et diminuer leur empreinte hydrique et les déchets associés. C'est aussi une excellente façon de faire face aux situations d'urgence associées aux changements climatiques, telles les difficultés d'accès à l'eau, puisque l'enfant allaité est mieux protégé que celui alimenté avec des PCN. Pour s'assurer que la protection offerte par l'allaitement puisse se concrétiser, nous présentons des éléments pouvant aider les décideurs à saisir une opportunité prometteuse : améliorer le soutien à l'alimentation infantile pour les femmes et les familles.

"Stronger with Breastmilk Only" Initiative in 5 African Countries: Case Study on the Implementation Process and Contribution to the Enabling Environment for Breastfeeding.

Background: The practice of giving water before 6 mo of age is the biggest barrier to exclusive breastfeeding in West and Central Africa. To address this challenge, a regional initiative, "Stronger with Breastmilk Only" (SWBO), was rolled out at country level in several countries of the region. Objective: We examined the implementation process of the SWBO initiative and the contribution of its advocacy component to a more supportive environment for breastfeeding policies and programs. Methods: This study was based on 2 assessments at the national level carried out in 5 countries (Burkina Faso, Chad, Democratic Republic of the Congo, Senegal, and Sierra Leone) using qualitative methods. We combined 2 evaluative approaches (contribution analysis and outcome harvesting) and applied 2 theoretical lenses (Breastfeeding Gear Model and Consolidated Framework for Implementation Research) to examine the implementation process and the enabling environment for breastfeeding. Data sources included ∼300 documents related to the initiative and 43 key informant interviews collected between early 2021 and mid-2022. Results: First, we show how a broad initiative composed of a set of combined interventions targeting multiple levels of determinants of breastfeeding was set up and implemented. All countries went through a similar pattern of activities for the implementation process. Second, we illustrate that the initiative was able to foster an enabling environment for breastfeeding. Progress was achieved notably on legislation and policies, coordination, funding, training and program delivery, and research and evaluation. Third, through a detailed contribution story of the case of Burkina Faso, we illustrate more precisely how the initiative, specifically its advocacy component, contributed to this progress. Conclusion: This study shed light on how an initiative combining a set of interventions to address determinants of breastfeeding at multiple levels can be implemented regionally and contributes to fostering an enabling environment for breastfeeding at scale.

Placenta Accreta Spectrum Disorders: A National Survey.

OBJECTIVES: Describe the current practice of Canadian obstetricians-gynaecologists in managing placenta accreta spectrum (PAS) disorders from suspicion of diagnosis to delivery planning and explore the impact of the latest national practice guidelines on this topic. METHODS: We distributed a cross-sectional bilingual electronic survey to Canadian obstetricians-gynaecologists in March-April 2021. Demographic data and information on screening, diagnosis, and management were collected using a 39-item questionnaire. The survey was validated and pretested among a sample population. Descriptive statistics were used to present the results. RESULTS: We received 142 responses. Almost 60% of respondents said they had read the latest Society of Obstetricians and Gynaecologists of Canada clinical practice guideline on PAS disorders, published in July 2019. Nearly 1 in 3 respondents changed their practice following this guideline. Respondents highlighted the importance of 4 key points: (1) limiting travel to thereby remain close to a regional care centre, (2) preoperative anemia optimization, (3) performance of cesarean-hysterectomy leaving the placenta in situ (83%), (4) access via midline laparotomy (65%). Most respondents recognized the importance of perioperative blood loss reduction strategies such as tranexamic acid and perioperative thromboprophylaxis via sequential compression devices and low-molecular-weight heparin until full mobilization. CONCLUSIONS: This study demonstrates the impact of the Society of Obstetricians and Gynaecologists of Canada's PAS clinical practice guideline on management choices made by Canadian clinicians. Our study highlights the value of a multidisciplinary approach to reducing maternal morbidity in individuals facing surgery for a PAS disorder and the importance of regionalized care that is resourced to provide maternal-fetal medicine and surgical expertise, transfusion medicine, and critical care support.

Understanding the challenges related to breastfeeding education and barriers to curricular change: a systems perspective for transforming health professions education.

Objectives: A majority of women and families wish that their babies be breastfed. However, too many still receive insufficient or inappropriate initial care from health professionals (HPs) who have limited breastfeeding (BF) competencies. We investigated barriers and potential solutions to improve the undergraduate training programs for various HPs. Methods: Focus groups were carried out in three universities in Quebec and one in Ontario (Canada), with 30 faculty and program directors from medicine, midwifery, nursing, nutrition, and pharmacy. Discussions were subjected to thematic content analysis, before being validated in a strategic planning workshop with 48 participants from the same disciplines, plus dentistry and chiropractic. Findings: Substantive improvements of undergraduate training programs for BF could be obtained by addressing challenges related to the insufficient, or lack of, (i) interactions among various HPs, (ii) opportunities for practical learning, (iii) specific standards to guide course content, (iv) real-life experience with counselling, and (v) understanding of the influence of attitudes on professional practice. Several potential solutions were proposed and validated. The re-interpretation of the results in light of various literature led to an emerging framework that takes a systems perspective for enhancing the education of HPs on BF. Conclusions: To improve the education of HPs so as to enable them to provide relevant support for future mothers, mothers and their families, solutions need to be carried out to address challenges in the health system, the education system as well as regarding the curricular change process.

Objectifs: La majorité des femmes et des familles souhaitent que leur bébé soit allaité. Toutefois, plusieurs ne reçoivent pas un soutien adéquat de la part de professionnels de la santé (PS) qui ont des compétences limitées en allaitement. Nous avons étudié les barrières et les solutions potentielles en vue de rehausser la formation initiale de divers PS. Méthodes: Des groupes de discussion ont été organisés dans trois universités du Québec et une en Ontario (Canada) avec 30 directeurs de programmes et membres du corps professoral en médecine, pratique sage-femme, sciences infirmières, nutrition et pharmacie. Les discussions ont fait l'objet d'une analyse de contenu thématique laquelle fut ensuite validée dans un atelier de planification stratégique avec 48 participants des mêmes disciplines auxquelles se sont ajoutées dentisterie et chiropratique. Résultats: Des améliorations substantielles des compétences en allaitement dans les programmes de formation initiale pourraient être obtenues en travaillant sur les défis associés à l'insuffisance, ou à l'absence de, (i) interactions entre les divers PS, (ii) opportunités d'apprentissages pratiques, (iii) normes spécifiques pour guider les contenus de cours, (iv) expériences réelles avec le counseling, et (v) compréhension de l'influence des attitudes sur la pratique professionnelle. La ré-interprétation des résultats à la lumière de la littérature a fait émerger un cadre conceptuel avec une perspective systémique pour guider le rehaussement de la formation en allaitement des divers PS. Conclusions: Afin d'améliorer la formation des PS pour qu'ils/elles puissent fournir un soutien pertinent aux futures mères, aux mères et à leurs familles, des solutions visant à la fois les défis dans le système de santé, dans le système d'éducation et dans le processus de changement curriculaire doivent être mises en œuvre.

Countries' experiences scaling up national breastfeeding, protection, promotion and support programmes: Comparative case studies analysis.

Scaling up effective interventions, policies and programmes can improve breastfeeding (BF) outcomes. Furthermore, considerable interest exists in learning from relatively recent successful efforts that can inform further scaling up, with appropriate adaptations, across countries. The purpose of this four-country case studies analysis was to examine why and how improvements in BF practices occurred across four contrasting countries; Burkina Faso, the Philippines, Mexico and the United States of America. Literature reviews and key informant interviews were conducted to document BF trends over time, in addition to why and how BF protection, promotion and support policies and programmes were implemented at a national level. A qualitative thematic analysis was conducted. The 'Breastfeeding Gear Model' and RE-AIM (Reach; Effectiveness; Adoption; Implementation; and Maintenance) frameworks were used to understand and map the factors facilitating or hindering the scale up of the national programmes and corresponding improvements in BF practices. Each of the studied countries had different processes and timing to implement and scale up programmes to promote, protect and support breastfeeding. However, in all four countries, evidence-based advocacy, multisectoral political will, financing, research and evaluation, and coordination were key to fostering an enabling environment for BF. Furthermore, in all countries, lack of adequate maternity protection and the aggressive marketing of the breast-milk substitutes industry remains a strong source of negative feedback loops that are undermining investments in BF programmes. Country-specific best practices included innovative legislative measures (Philippines), monitoring and evaluation systems (United States of America), engagement of civil society (Mexico) and behavior change communication BF promotion (Burkina Faso) initiatives. There is an urgent need to improve maternity protection and to strongly enforce the WHO Code of Marketing of Breast-Milk Substitutes.

Operationalizing Implementation Science in Nutrition: The Implementation Science Initiative in Kenya and Uganda.

BACKGROUND: Implementation science (IS) has the potential to improve the implementation and impact of policies, programs, and interventions. Most of the training, guidance, and experience has focused on implementation research, which is only 1 part of the broader field of IS. In 2018, the Society for Implementation Science in Nutrition borrowed concepts from IS in health to develop a broader and more integrated conceptual framework, adapted to the particular case of nutrition and with language and concepts more familiar to the nutrition community: it is called the IS in Nutrition (ISN) framework. OBJECTIVE: The purpose of this research was to generate knowledge concerning challenges and strategies in operationalizing the ISN framework in low- and middle-income country (LMIC) settings. METHODS: The ISN framework was operationalized in partnership with country teams in Kenya and Uganda over a 3-y period as part of the Implementation Science Initiative. An action research methodology (developmental evaluation) was used to provide timely feedback to the country teams, facilitate adaptations and adjustments, and generate the data presented in this article concerning challenges and strategies. RESULTS: Operationalization of the ISN framework proceeded by first articulating a set of guiding principles as touchstones for the country teams and further articulating 6 components of an IS system to facilitate development of work streams. Challenges and strategies in implementing these 6 components were then documented. The knowledge gained through this experience led to the development of an IS system operational model to assist the application of IS in other LMIC settings. CONCLUSIONS: Future investments in IS should prioritize a system- and capacity-building approach in order to realize its full potential and become institutionalized at country level. The operational model can guide others to improve the implementation of IS within a broad range of programs.

Improving Iron and Folic Acid Supplementation Among Pregnant Women: An Implementation Science Approach in East-Central Uganda.

INTRODUCTION: To address maternal iron-deficiency anemia and low uptake of iron and folic acid supplementation (IFAS) among antenatal care (ANC) clinic attendees in East-Central Uganda, the Anemia Implementation Science Initiative embedded enhanced quality improvement (QI) activities into an integrated health project utilizing QI methodologies. METHODS: To address 2 bottlenecks of stock-outs and inadequate health education for pregnant women during ANC, an enhanced QI intervention was implemented from July 2019 to September 2020 in 2 districts. We conducted a mixed-methods effectiveness quasi-experimental study to assess whether the intervention increased the availability of IFAS in the intervention districts. We used longitudinal facility-level data from 2 treatment districts and 1 comparison district for the quantitative results. Difference-in-difference estimation was used to measure the impact of the intervention on IFAS health education and IFA availability at the health facility. We used logistic regression modeling to control for factors associated with IFAS uptake and potential differences in baseline values. Researchers conducted exit interviews with ANC clients and in-depth interviews with providers and district managers for greater insights into the implementation process. RESULTS: The intervention increased the probability, at a statistically significant level, of pregnant women both receiving IFAS and receiving health education on IFAS during ANC. According to inter-viewees, the intervention approach improved stakeholder engagement and buy-in, which brought about change at all levels of the health system. DISCUSSION: The intervention successfully addressed the 2 main bottlenecks to availability of IFAS for pregnant women attending ANC-inadequate provision of IFAS education and a weak drug quantification process. Even without additional funds to purchase commodities, this approach improved district capacity to advocate for and manage IFAS commodities. It could also be used to strengthen overall ANC quality.

Breast feeding after caesarean delivery on maternal request: protocol of a systematic review and meta-analysis.

INTRODUCTION: Caesarean delivery under maternal request (CDMR) is a major factor contributing to the rising global rates of caesarean section (CS) procedure. The choice of CDMR without medical indications could provide a sense of assured safety by avoiding the experiences and complications of vaginal birth, and the risks related to an emergency CS. However, it might adversely influence women's breast feeding patterns and produce a long-lasting impact on maternal and neonatal health. This study aims to systematically review the current evidence relating to the effects of intentions of performing CDMR on breast feeding. METHODS AND ANALYSIS: A comprehensive literature search will be performed in three English-language electronic databases, major clinical study registries and other sources for original studies reporting the breast feeding outcomes after a planned CDMR or vaginal delivery. The three databases Medline, Embase and the Cochrane Central Register of Controlled Trials will be searched via Ovid from inception to February 2020. Randomised controlled trials (RCTs), pseudo-RCTs, cohort studies and case-control studies on this topic will be included. Participants in the experimental or case group should meet the Robson criteria of classes 2B or 4B and have experienced planned CS undertaken for no maternal or foetal indication, whereas participants in the control group have undergone scheduled vaginal delivery. All kinds of breast feeding outcomes will be included. Meta-analyses will be attempted to provide an estimate of the pooled effect and will be stratified by different study designs. A qualitative description will be provided if quantitative synthesis proves to be fruitless. ETHICS AND DISSEMINATION: This study is a secondary literature review that does not need ethical approval. No primary data will be collected from the participants. Findings of this study will be presented at scientific conferences and be published in scientific journals. PROSPERO REGISTRATION NUMBER: CRD42020160303.

A whole-food, plant-based nutrition program: Evaluation of cardiovascular outcomes and exploration of food choices determinants.

OBJECTIVES: An ideal diet to prevent cardiovascular diseases contains an unlimited intake of various plant foods and a reduced intake of animal and highly processed foods. Researchers have reported that nutrition education programs that prioritize whole-plant foods effectively contribute to the prevention of unhealthy cardiovascular outcomes. We examined whether a 12-wk nutrition education program in adults from Montreal (Quebec, Canada) with at least one risk factor of cardiovascular disease was effective in modifying their eating patterns toward including more whole-plant foods. We further evaluated the effects of this program on participants' cardiovascular outcomes and explored determinants influencing food choices toward whole-food, plant-based diets. METHODS: A sequential, explanatory, mixed-methods, research design was used. A quantitative step (i.e., single-arm, quasi-experimental trial) preceded participant recruitment for a qualitative phase (i.e., phenomenological study; semistructured interview; thematic analysis). The examined outcomes were changes in cardiovascular risk factors (paired t tests) and determinants of food choice (thematic analysis). RESULTS: Weight (-10.5 lbs; 95% confidence interval [CI]: -9.0 to -12.0), waist circumference (-7.4 cm; 95% CI: -6.5 to -8.4), total cholesterol (-0.87 mmol/L; 95% CI: -0.57 to -1.17), and low-density lipoprotein cholesterol (-29.7% or -0.84 mmol/L; 95% CI: -0.55 to -1.13) all improved significantly (P ˂ 0.001). Encouraging ad libitum intake of various whole-food plant-based items appealed more to participants than traditional strategies. Altruistic and societal motives, in addition to health, were identified as key determinants of an increased adoption of whole-food plant-based diets. CONCLUSIONS: The whole-food, plant-based nutrition program improves cardiovascular health in adults and features characteristics that may inform future nutrition programs and public health interventions.

A comparison of exclusive breastfeeding in Belgian maternity facilities with and without Baby-friendly Hospital status.

A retrospective cross-sectional study was carried out in Wallonia (the southern region of Belgium) in which a 20-question breastfeeding (BF) module was included in an immunization survey. The purpose of this paper is to compare exclusive breastfeeding (EBF) prevalences and BF practices for mothers giving birth in Baby-friendly Hospital Initiative (BFHI) and non-BFHI maternity facilities. A total of 557 mothers responded to BF questions when their child was 18-24 months old; 26.7% of them delivered in a BFHI maternity facility. At discharge, a larger proportion of children were exclusively breastfed if they were born in a BFHI maternity facility (76.5% vs. 65.8%, p = .02). The median duration of EBF (15.0 vs. 12.9 weeks, p = .3), and the proportion of children exclusively breastfed at 5 months (16.8% vs 15.8%, p = 1.0) were similar in both groups. Few mothers knew that EBF was recommended for the first 6 months of life (28.6% in BFHI vs 23.1% in non-BFHI, p = .2). For most groups of the population examined, the rates of BF tended to be higher in BFHI facilities, but many differences were not significant. More specifically, BFHI seemed to boost BF practices among mothers more likely to breastfeed, but the Initiative did not seem to trigger enhanced BF practices in mothers traditionally less likely to breastfeed (except for indifferent/negative partner's attitude and mothers of Belgian origin). Influencing the BF practices of mothers less likely to breastfeed requires a special attention with complementary actions in maternity facilities as well as in community services.

Strengthening advocacy and policy change for infant and young child feeding.

The creation of environments that are more supportive of optimal infant and young child feeding (IYCF) requires countries to enact policies, such as those related to the Maternity Protection Convention, the International Code of Marketing of Breast-milk Substitutes (the Code), and the Baby-Friendly Hospital Initiative. However, challenges are experienced in the translation of international policy standards into national legal measures, and there is an important gap in understanding how countries achieve progress. Policy advocacy is a nearly universal feature, but there are methodological challenges and few studies evaluating strategies and effects. The purpose of this supplement to Maternal & Child Nutrition is to address those gaps. This supplement contains three papers that present findings from a real-time evaluation of the advocacy efforts of Alive & Thrive (A&T), United Nations International Children's Emergency Fund (UNICEF), and partners, that sought to support governments in fostering enabling environment for optimal IYCF in Southeast Asia (SEA) and Africa. A combination of two emergent, theory-based evaluation approaches was used: developmental evaluation and contribution analysis. The overall objective of the evaluation was to document the extent to which policy objectives were or were not achieved in each country and to identify the key drivers of policy change. One contribution of the supplement is a distinction between and illustration of triggers and drivers of policy change. Three main drivers of policy change were identified: (a) the use of an explicit advocacy approach; (b) the creation of a strategic group of actors; and (c) the realization of 15 critical tasks (more specifically for the Code). Each of the critical tasks has been identified as having triggered progress on the Code in those countries. This supplement provides evidence that the advocacy efforts of A&T, UNICEF, and partners contributed to enhanced IYCF policies in SEA and reveals how it helped to achieve progress. The insights contained in this supplement can serve as a guide for policy advocates for enhanced IYCF policies. A short communication puts findings into perspective within global context.

Translating the International Code of Marketing of Breast-milk Substitutes into national measures in nine countries.

The International Code of Marketing of Breast-milk Substitutes (the Code) adopted by the World Health Assembly (WHA) in 1981 and regularly updated through subsequent WHA resolutions, represents the international policy framework for protecting breastfeeding against inappropriate marketing practices. By March 2016, at least 135 countries had some measures covering provisions of the Code in their legislation. The translation of the International Code into national measures was investigated in the context of the advocacy efforts undertaken by the Alive & Thrive (A&T) initiative with UNICEF and partners. A real-time evaluation was carried out over 22 months in seven Southeast Asian countries (Cambodia, Indonesia, Lao People's Democratic Republic [Lao PDR], Myanmar, Thailand, Vietnam, and Timor-Leste) and two African countries (Burkina Faso and Ethiopia). Drivers of policy change and progress were examined. Two theory-based approaches were used: developmental evaluation and contribution analysis. Data collection methods included participant observation, key informant meetings, in-depth interviews, reflective practice, and desk review. Overall, countries made significant progress in translating the International Code into national measures and in moving forward throughout the policy cycle. The main driver of policy change was the creation of a strategic group, which engaged key relevant actors and supported the government in the performance of 15 critical tasks, which the analysis reveals is a second driver. Those critical tasks are described in this paper and could help public health advocates to anticipate the stages and challenges of policy change and develop more effective strategies to translate the Code into their legal framework.

Contribution of the Alive & Thrive-UNICEF advocacy efforts to improve infant and young child feeding policies in Southeast Asia.

Evaluating the impact of advocacy for policy change presents many challenges. Recent advances in the field of evaluation, such as contribution analysis (CA), offer guidance on how to make credible claims regarding such impact. The purposes of this article are (a) to detail the application of CA to assess the contribution of an advocacy initiative to improve infant and young child feeding policies and (b) to present the emergent theory of change and contribution story of how progress was achieved. An evaluation applying developmental evaluation and CA was conducted on the Alive & Thrive (A&T)-UNICEF initiative in seven Southeast Asian countries to document the extent to which policy objectives were achieved and identify key drivers of policy change. A contribution story was developed based on these experiences. The advocacy approach, which involved a four-part process, contributed directly to (a) set the agenda of various actors and (b) create a strategic group; and indirectly to (a) set and maintain the issue on the agenda at all stages of the policy cycle, (b) support the government to carry out a set of critical tasks, and (c) extend commitment. All of this helped to achieve progress towards policy change. External influences were at play. The flexibility of A&T allowed key actors to utilize the positive external influences and address some of the negative ones through developing responsive strategies mitigating their effects. The emerging contribution story supports that A&T-UNICEF initiative contributed to the progress achieved in the participating countries.

Enhancing governance and strengthening advocacy for policy change of large Collective Impact initiatives.

Nutrition issues are increasingly being addressed through global partnerships and multi-sectoral initiatives. Ensuring effective governance of these initiatives is instrumental for achieving large-scale impact. The Collective Impact (CI) approach is an insightful framework that can be used to guide and assess the effectiveness of this governance. Despite the utility and widespread use of this approach, two gaps are identified: a limited understanding of the implications of expansion for an initiative operating under the conditions of CI and a lack of attention to advocacy for policy change in CI initiatives. In this paper, a case study was undertaken in which the CI lens was applied to the advocacy efforts of Alive & Thrive (A&T), UNICEF and partners. The initiative expanded into a regional movement and achieved meaningful policy changes in infant and young child feeding policies in seven countries in Southeast Asia. These efforts are examined in order to address the two gaps identified in the CI approach. The objectives of the paper are (a) to examine the governance of this initiative and the process of expansion from a national to a regional, multilayered initiative, with attention to challenges, adaptations, and key elements, and (b) to compare advocacy in the A&T-UNICEF initiative and in typical CI initiatives and gain insight into how the practice of advocacy for policy change can be strengthened in CI initiatives.

RAN nucleo-cytoplasmic transport and mitotic spindle assembly partners XPO7 and TPX2 are new prognostic biomarkers in serous epithelial ovarian cancer.

PURPOSE: Epithelial ovarian cancer has the highest mortality rate of all gynecological malignancies. We have shown that high RAN expression strongly correlates with high-grade and poor patient survival in epithelial ovarian cancer. However, as RAN is a small GTPase involved in two main biological functions, nucleo-cytoplasmic transport and mitosis, it is still unknown which of these functions associate with poor prognosis. METHODS: To examine the biomarker value of RAN network components in serous epithelial ovarian cancer, protein expression of six specific RAN partners was analyzed by immunohistochemistry using a tissue microarray representing 143 patients associated with clinical parameters. The RAN GDP/GTP cycle was evaluated by the expression of RANBP1 and RCC1, the mitotic function by TPX2 and IMPß, and the nucleo-cytoplasmic trafficking function by XPO7, XPOT and IMPß. RESULTS: Based on Kaplan-Meier analyses, RAN, cytoplasmic XPO7 and TPX2 were significantly associated with poor overall patient survival, and RAN and TPX2 were associated with lower disease free survival in patients with high-grade serous carcinoma. Cox regression analysis revealed that RAN and TPX2 expression were independent prognostic factors for both overall and disease free survival, and that cytoplasmic XPO7 expression was a prognostic factor for overall patient survival. CONCLUSIONS: In this systematic study, we show that RAN and two protein partners involved in its nucleo-cytoplasmic and mitotic functions (XPO7 and TPX2, respectively) can be used as biomarkers to stratify patients based on prognosis. In particular, we reported for the first time the clinical relevance of the exportin XPO7 and showed that TPX2 expression had the strongest prognostic value. These findings suggest that protein partners in each of RAN's functions can discriminate between different outcomes in high-grade serous epithelial ovarian cancer patients. Furthermore, these proteins point to cellular processes that may ultimately be targeted to improve the survival in serous epithelial ovarian cancer.

Derivation and characterization of matched cell lines from primary and recurrent serous ovarian cancer.

BACKGROUND: Cell line models have proven to be effective tools to investigate a variety of ovarian cancer features. Due to the limited number of cell lines, particularly of the serous subtype, the heterogeneity of the disease, and the lack of cell lines that model disease progression, there is a need to further develop cell line resources available for research. This study describes nine cell lines derived from three ovarian cancer cases that were established at initial diagnosis and at subsequent relapse after chemotherapy. METHODS: The cell lines from three women diagnosed with high-grade serous ovarian cancer (1369, 2295 and 3133) were derived from solid tumor (TOV) and ascites (OV), at specific time points at diagnosis and relapse (R). Primary treatment was a combination of paclitaxel/carboplatin (1369, 3133), or cisplatin/topotecan (2295). Second line treatment included doxorubicin, gemcitabine and topotecan. In addition to molecular characterization (p53, HER2), the cell lines were characterized based on cell growth characteristics including spheroid growth, migration potential, and anchorage independence. The in vivo tumorigenicity potential of the cell lines was measured. Response to paclitaxel and carboplatin was assessed using a clonogenic assay. RESULTS: All cell lines had either a nonsense or missense TP53 mutations. The ability to form compact spheroids or aggregates was observed in six of nine cell lines. Limited ability for migration and anchorage independence was observed. The OV3133(R) cell line, formed tumors at subcutaneous sites in SCID mice. Based on IC50 values and dose response curves, there was clear evidence of acquired resistance to carboplatin for TOV2295(R) and OV2295(R2) cell lines. CONCLUSION: The study identified nine new high-grade serous ovarian cancer cell lines, derived before and after chemotherapy that provides a unique resource for investigating the evolution of this common histopathological subtype of ovarian cancer.

Role of proline 1150 in functional interactions between the membrane spanning domains and nucleotide binding domains of the MRP1 (ABCC1) transporter.

The ATP-binding cassette multidrug resistance protein 1 (MRP1) mediates ATP-dependent cellular efflux of drugs and organic anions. We previously described a mutant, MRP1-Pro1150Ala, which exhibits selectively increased estradiol glucuronide (E217betaG) and methotrexate transport as well as altered interactions with ATP. We have now further explored the functional importance of MRP1-Pro1150 at the interface of transmembrane helix 15 and cytoplasmic loop 7 (CL7) by replacing it with Gly, Ile, Leu and Val. All four mutants exhibited a phenotype similar to MRP1-Pro1150Ala with respect to organic anion transport and [gamma32P]8N3ATP photolabeling. They also displayed very low levels of substrate-independent vanadate-induced trapping of [alpha32P]8N3ADP. To better understand the relationship between the altered nucleotide interactions and transport activity of these mutants, [alpha32P]8N3ADP trapping experiments were performed under different conditions. Unlike leukotriene C4, E217betaG decreased [alpha32P]8N3ADP trapping by both wild-type and mutant MRP1. [alpha32P]8N3ADP trapping by MRP1-Pro1150Ala could be increased by using Ni2+ instead of Mg2+, and by decreasing temperature; however, the transport properties of the mutant remained unchanged. We conclude that the reduced [alpha32P]8N3ADP trapping associated with loss of Pro1150, or the presence of E217betaG, is due to enhanced ADP release following ATP hydrolysis rather than a reduction in ATP hydrolysis itself. We hypothesize that loss of Pro1150 alters the role of CL7 as a coupling helix that mediates signaling between the nucleotide binding domains and some substrate binding sites in the membrane spanning domains of MRP1.

Successful treatment of encapsulating peritoneal sclerosis with immunosuppressive therapy.

Encapsulating peritoneal sclerosis is a rare, but potentially lethal, complication of peritoneal dialysis. Treatment of patients with encapsulating peritoneal sclerosis is controversial. Conservative treatment carries a poor outcome, and immunosuppressive drugs are now used frequently. Most commonly, these immunosuppressive regimens include steroids with or without azathioprine or cyclosporine. Mycophenolate mofetil is a reversible DNA synthesis inhibitor that frequently replaces azathioprine in renal transplantation because of its improved immunosuppressive potency and better side-effect profile. We report 3 cases of encapsulating peritoneal sclerosis in continuous ambulatory peritoneal dialysis patients for which an association of prednisone and mycophenolate mofetil significantly modified the evolution of the disease. All 3 patients showed significant improvement within a month and are still alive more than 2 years after the diagnosis of encapsulating peritoneal sclerosis. None experienced a relapse or abdominal symptoms, and body weights are stable. This is the first report of 3 cases of successful treatment of patients with encapsulating peritoneal sclerosis with prednisone and mycophenolate mofetil.

Mutational analysis of a highly conserved proline residue in MRP1, MRP2, and MRP3 reveals a partially conserved function.

The ATP-binding cassette multidrug resistance protein 1 MRP1 (ABCC1) mediates the cellular efflux of organic anions including conjugated metabolites, chemotherapeutic agents, and toxicants. We previously described a mutation in cytoplasmic loop 7 (CL7) of MRP1, Pro1150Ala, which reduced leukotriene C(4) (LTC(4)) transport but increased 17beta-estradiol 17beta-d-glucuronide (E(2)17betaG) and methotrexate (MTX) transport. Vanadate-induced trapping of [alpha-(32)P]8N(3)ADP by the Pro1150Ala mutant in the absence of substrate was also greatly reduced compared with wild-type MRP1 suggesting an uncoupling of ATP hydrolysis and transport activity. To determine whether the functional importance of MRP1-Pro(1150) is conserved, the analogous Pro(1158) and Pro(1147) residues in the MRP2 and MRP3 transporters, respectively, were mutated to Ala. Expression levels of the three mutants were unaffected; however, the vesicular transport activity of at least one organic anion substrate was significantly altered. As observed for MRP1-Pro1150Ala, LTC(4) transport by MRP2-Pro1158Ala was decreased. However, E(2)17betaG and MTX transport was comparable with that of wild-type MRP2 rather than increased as was observed for MRP1-Pro1150Ala. In the case of MRP3-Pro1147Ala, LTC(4) transport was increased, whereas E(2)17betaG transport was unaffected. MTX transport by MRP3-Pro1147Ala was also increased but to a lesser extent than for MRP1-Pro1150Ala. In contrast, all three mutants showed a marked reduction in levels of vanadate-induced trapped [alpha-(32)P]8N(3)ADP. We conclude that MRP1-Pro(1150), MRP2-Pro(1158), and MRP3-Pro(1147) in CL7 differ in their influence on substrate specificity but share a common role in the nucleotide interactions of these transporters.