Maternal obesity and the impact of associated early-life inflammation on long-term health of offspring.

The prevalence of obesity is increasingly common in the United States, with ~25% of women of reproductive age being overweight or obese. Metaflammation, a chronic low grade inflammatory state caused by altered metabolism, is often present in pregnancies complicated by obesity. As a result, the fetuses of mothers who are obese are exposed to an in-utero environment that has altered nutrients and cytokines. Notably, both human and preclinical studies have shown that children born to mothers with obesity have higher risks of developing chronic illnesses affecting various organ systems. In this review, the authors sought to present the role of cytokines and inflammation during healthy pregnancy and determine how maternal obesity changes the inflammatory landscape of the mother, leading to fetal reprogramming. Next, the negative long-term impact on offspring's health in numerous disease contexts, including offspring's risk of developing neuropsychiatric disorders (autism, attention deficit and hyperactive disorder), metabolic diseases (obesity, type 2 diabetes), atopy, and malignancies will be discussed along with the potential of altered immune/inflammatory status in offspring as a contributor of these diseases. Finally, the authors will list critical knowledge gaps in the field of developmental programming of health and diseases in the context of offspring of mothers with obesity, particularly the understudied role of hematopoietic stem and progenitor cells.

Complex decongestive therapy in a patient with poliomyelitis, bilateral lymphoedema and a deep wound: a case study.

OBJECTIVE: The aim of this case report is to describe the results of complex decongestive therapy (CDT) in a patient with poliomyelitis and bilateral lymphoedema, and to emphasise the effect of CDT on wound healing. METHOD: A 48-year-old female patient was given CDT for bilateral grade 3 lymphoedema in the lower extremities and a deep wound on the right foot. She had been diagnosed with poliomyelitis sequela and mobilised with a wheelchair for 26 years. The lymphoedema on both legs and the wound on the right foot sole had been present for five years and eight months, respectively. Detailed wound care had been performed previously upon the green, malodorous infected wound, without healing. The patient received skin care education, manual lymphatic drainage, multilayer bandaging and exercises for 4 weeks in a total of 20 sessions. The improvement was assessed by limb volumes prior to and at the end of the treatments. RESULTS: The right and left lower limb volumes were decreased significantly at the end of treatments (3042cm³ (R) and 3165cm³ (L) before versus 2702cm3 (R) and 2401cm3 (L) afterward). The wound size decreased considerably and the green malodorous flow ceased. The patient continued self-massage and self-bandaging after hospital discharge. The control follow-up, one month later, revealed a completely healed wound with maintained volume. CONCLUSION: In conclusion CDT for a duration of 4 weeks in a female patient with poliomyelitis, bilateral lymphoedema and an infectious hard-to-heal wound, improved both the lymphoedema and wound healing.

Upper Extremity Lymphedema Related to Everolimus in a Renal Transplant Recipient: Efficacy of Complete Decongestive Therapy.

We report our experience with a new case of lymphedema of the upper extremity in a renal transplant recipient under treatment with everolimus immunosuppression, and we emphasize the effects of complete decongestive therapy on this chronic condition.

GATA3 as a master regulator for interactions of tumor-associated macrophages with high-grade serous ovarian carcinoma.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic cancer. Emerging evidence suggests that tumor-associated macrophages (TAMs) play an immunosuppressive role in the tumor microenvironment and promote tumor growth, angiogenesis, and metastasis in ovarian cancer. Therefore, targeting TAMs in patients with ovarian cancer is an appealing strategy; however, all trials to date have failed. To improve the efficacy of this approach, we sought to elucidate the underlying mechanisms of the role of TAMs in ovarian cancer. We found that the developmental transcription factor GATA3 was highly expressed in HGSOC cell lines but not in the fallopian tube, which is the main origin of HGSOC. GATA3 expression was associated with poor prognosis in HGSOC patients (P < .05) and was found to promote proliferation and migration in HGSOC cell lines. GATA3 was released abundantly from TAM cells via exosomes and contributed to tumor growth in the tumor microenvironment. Moreover, GATA3 acted as a regulator for macrophage polarization and interactions between TAMs and HGSOC to support proliferation, motility, and cisplatin chemoresistance in mutant TP53 HGSOC cell lines. Furthermore, GATA3 played a critical role in the interactions between TAMs and mutant TP53 HGSOC to promote angiogenesis and epithelial-mesenchymal transition with epigenetic regulation. Targeting GATA3 using GATA3siRNA in TAMs impeded GATA3-driven proliferation, migration, cisplatin chemoresistance, and angiogenesis in mutant TP53 HGSOC cell lines. Our findings indicate that GATA3 plays a novel role in immunoediting of HGSOC and demonstrate that GATA3 may serve as a prognostic marker for HGSOC and a promising target in the treatment of HGSOC.

The Reliability and Validity of Lymphedema Quality of Life Questionnaire-Leg in Turkish Patients with Lower Limb Lymphedema.

Background: Accurate information on quality of life (QoL) outcomes among patients with lower limb lymphedema (LLL) is substantially needed to capture lymphedema-specific impairments and make clinical decisions for the management of this suffering condition. No specific instrument for QoL in patients with LLL has been translated to Turkish and validated. This study aims to adapt the Lymphedema Quality of Life Questionnaire-leg (LYMQOL-Leg) to Turkish and to test its reliability and validity in patients with LLL. Methods and Results: The Turkish-LYMQOL-Leg was obtained using forward-backward translation and administered to 138 patients with LLL, along with Short Form 36 (SF-36), and Lower Extremity Functional Scale (LEFS), between May 2015 and October 2017. A test-retest interval of 7 days was used to assess the reliability. Descriptive analysis was applied for demographic variables and validation studies were conducted by means of construct validity using Spearman's rank correlation coefficient. Internal consistency and test-retest reliability were assessed using Cronbach's α and intraclass correlation coefficient (ICC), respectively. All patients with LLL completed the questionnaires. The mean age and lymphedema duration were 52.01 ± 14.73 years and 95.6 ± 108.6 months, respectively. Internal consistency and test-retest reliability of the Turkish-LYMQOL-Leg were good with Cronbach's α (0.85-0.90) and test-retest ICC (0.68-0.85). External construct validity was highly confirmed by expected correlations with comparator scales SF-36 and LEFS (p < 0.01). Conclusion: The Turkish version of the LYMQOL-Leg is a valid and reliable tool for evaluating QoL in patients with LLL that can readily be applied as an outcome measure both in clinical practice and research studies.

Hypermobility Frequency in School Children: Relationship With Idiopathic Scoliosis, Age, Sex and Musculoskeletal Problems.

Objectives: This study aims to assess the prevalence of generalized joint hypermobility (GJH) in school children in relation to scoliosis and to identify musculoskeletal problems. Patients and methods: This cross-sectional study included 822 school children (413 males, 409 females; mean age 12.2±1.3 years; range, 10 and 15 years). Demographic characteristics of all children were recorded. The presence of GJH was assessed by the Beighton score (≥4 was considered joint hypermobility). Scoliosis screening consisted of forward bend test (FBT) and measurement of angle of trunk rotation (ATR). Positive FBT or ATR ≥5° was referred to a portable X-ray device. The presence of musculoskeletal complaints was determined by a questionnaire. Results: Children's Body Mass Index (BMI) was 19.6±4.1. GJH was diagnosed in 151 subjects (18.4%). No significant association was detected between sex and hypermobility. Joint hypermobility was inversely correlated with age and BMI. Scoliosis was found in 43 subjects (5.2%) and all of them except one girl had mild scoliosis. The most common scoliosis pattern was a single left thoracolumbar curve. Seventy-three subjects (8.9%) had Cobb angle under 10°, with a potential for progression. Among subjects having GJH, the most common clinical finding was pes planus (34.3%) and the most common clinical symptom was ankle sprain (31.3%). Conclusion: Similar to that found in children from many countries, GJH is a common clinical condition in Turkish children. GJH should be assessed in the differential diagnosis of adolescents with musculoskeletal complaints for effective treatment and reducing morbidity. GJH should be considered in adolescents with scoliosis, which may be an important aspect in treatment.

LIMPRINT Study: The Turkish Experience.

Background: Lymphedema and chronic edema is a major health care problem in both developed and nondeveloped countries The Lymphoedema Impact and Prevelance - International (LIMPRINT) study is an international health service-based study to determine the prevalence and functional impact in adult populations of member countries of the International Lymphoedema Framework (ILF). Methods and Results: A total of 1051 patients from eight centers in Turkey were recruited using the LIMPRINT study protocol. Data were collected using the core and module tools that assess the demographic and clinical properties as well as disability and quality of life (QoL). Most of the Turkish patients were recruited from specialist lymphedema services and were found to be women, housewives, and having secondary lymphedema because of cancer treatment. The duration of lymphedema was commonly <5 years and most of them had International Society of Lymphology (ISL) grade 2 lymphedema. Cellulitis, infection, and wounds were uncommon. The majority of patients did not get any treatment or advice before. Most of the patients had impaired QoL and decreased functionality, but psychological support was neglected. Although most had social health security access to lymphedema centers, nevertheless access seemed difficult because of distance and cost. Conclusion: The study has shown the current status and characteristics of lymphedema patients, treatment conditions, the unmet need for the diagnosis and treatment, as well as burden of the disease in both patients and families in Turkey. National health policies are needed for the prevention, diagnosis, and treatment in Turkey that utilize this informative data.

Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer.

BACKGROUND: Circulating miRNAs are known to play important roles in intercellular communication. However, the effects of exosomal miRNAs on cells are not fully understood. METHODS: To investigate the role of exosomal miR-1246 in ovarian cancer (OC) microenvironment, we performed RPPA as well as many other in vitro functional assays in ovarian cancer cells (sensitive; HeyA8, Skov3ip1, A2780 and chemoresistant; HeyA8-MDR, Skov3-TR, A2780-CP20). Therapeutic effect of miR-1246 inhibitor treatment was tested in OC animal model. We showed the effect of OC exosomal miR-1246 uptake on macrophages by co-culture experiments. FINDINGS: Substantial expression of oncogenic miR-1246 OC exosomes was found. We showed that Cav1 gene, which is the direct target of miR-1246, is involved in the process of exosomal transfer. A significantly worse overall prognosis were found for OC patients with high miR-1246 and low Cav1 expression based on TCGA data. miR-1246 expression were significantly higher in paclitaxel-resistant OC exosomes than in their sensitive counterparts. Overexpression of Cav1 and anti-miR-1246 treatment significantly sensitized OC cells to paclitaxel. We showed that Cav1 and multi drug resistance (MDR) gene is involved in the process of exosomal transfer. Our proteomic approach also revealed that miR-1246 inhibits Cav1 and acts through PDGFß receptor at the recipient cells to inhibit cell proliferation. miR-1246 inhibitor treatment in combination with chemotherapy led to reduced tumor burden in vivo. Finally, we demonstrated that when OC cells are co-cultured with macrophages, they are capable of transferring their oncogenic miR-1246 to M2-type macrophages, but not M0-type macrophages. INTERPRETATION: Our results suggest that cancer exosomes may contribute to oncogenesis by manipulating neighboring infiltrating immune cells. This study provide a new mechanistic therapeutic approach to overcome chemoresistance and tumor progression through exosomal miR-1246 in OC patients.

The reliability and validity of Lymphedema Quality of Life Questionnaire-Arm in Turkish patients with upper limb lymphedema related with breast cancer.

OBJECTIVES: This study aims to adapt Lymphedema Quality of Life Questionnaire-Arm (LYMQOL) into Turkish and to test its reliability and validity in Turkish patients with upper limb lymphedema related with breast cancer. PATIENTS AND METHODS: Between June 2015 and November 2015, the Turkish LYMQOL-Arm was obtained using forward-backward translation method and administered to a total of 135 female patients (mean age 51.8±9.8 years; range, 31 to 82 years) with upper limb lymphedema with European Organization for Research and Treatment of Cancer-QoL Breast Cancer-specific version (EORTC QLQ-BR23) and Functional Assessment of Cancer Therapy-Breast-4 (FACT-B+4) questionnaires. A test-retest interval of seven-days was used to assess the reliability. The validation studies were carried-out by means of construct-validity using Spearman's rank correlation-coefficient. Internal consistency and test-retest-reliability were assessed using Cronbach's alpha and intra-class correlation-coefficient (ICC), respectively. RESULTS: 135 patients completed the questionnaire with upper limb lymphedema related with breast cancer completed the questionnaires. The mean lymphedema duration was 21.1±28.7 (median: 6) months. Internal consistency and reliability of the Turkish LYMQOL-Arm was good with Cronbach's alpha (0.88-0.90) and test-retest ICC (0.45-0.71). External construct validity was highly confirmed by expected correlations with comparator scales, EORTCQLQ-BR23 and FACT-B+4 (p<0.01). CONCLUSION: The Turkish version of the LYMQOL-Arm is a valid and reliable tool for evaluating QoL in female patients with upper limb lymphedema related with breast cancer.

Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models.

Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK) has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER), and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.]) administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer.

Chitosan Nanoparticles for miRNA Delivery.

RNA interference techniques represent a promising strategy for therapeutic applications. In addition to small interfering RNA-based approaches, which have been widely studied and translated into clinical investigations, microRNA-based approaches are attractive owing to their "one hit, multiple targets" concept. To overcome challenges with in vivo delivery of microRNAs related to stability, cellular uptake, and specific delivery, our group has developed and characterized chitosan nanoparticles for nucleotide delivery. This platform allows for robust target modulation and antitumor activity following intravenous administration.

Exosomal miR-940 maintains SRC-mediated oncogenic activity in cancer cells: a possible role for exosomal disposal of tumor suppressor miRNAs.

Exosomes have emerged as important mediators of diverse biological functions including tumor suppression, tumor progression, invasion, immune escape and cell-to-cell communication, through the release of molecules such as mRNAs, miRNAs, and proteins. Here, we identified differentially expressed exosomal miRNAs between normal epithelial ovarian cell line and both resistant and sensitive ovarian cancer (OC) cell lines. We found miR-940 as abundant in exosomes from SKOV3-IP1, HeyA8, and HeyA8-MDR cells. The high expression of miR-940 is associated with better survival in patients with ovarian serous cystadenocarcinoma. Ectopic expression of miR-940 inhibited proliferation, colony formation, invasion, and migration and triggered G0/G1 cell cycle arrest and apoptosis in OC cells. Overexpression of miR-940 also inhibited tumor cell growth in vivo. We showed that proto-oncogene tyrosine-protein kinase (SRC) is directly targeted by miR-940 and that miR-940 inhibited SRC expression at mRNA and protein levels. Following this inhibition, the expression of proteins downstream of SRC, such as FAK, paxillin and Akt was also reduced. Collectively, our results suggest that OC cells secrete the tumor-suppressive miR-940 into the extracellular environment via exosomes, to maintain their invasiveness and tumorigenic phenotype.