Locoregional Anesthesia's Association With Reduced Intensive Care Unit Stay After Elective Endovascular Aneurysm Repair: Impact of Temporal Changes in Practice Patterns.

BACKGROUND: Elective endovascular aneurysm repair (EVAR) can be performed via local anesthetics and/or regional (epidural or spinal) anesthesia (locoregional [LR]), versus general anesthesia (GA), conferring reduced intensive care unit (ICU) and hospital stays. Current analyses fail to account for temporal changes in vascular practice. Therefore, this study aimed to confirm reductions in ICU and hospital stays among LR patients while accounting for changes in practice patterns. MATERIALS AND METHODS: Using the Society for Vascular Surgery's Vascular Quality Initiative, elective EVARs from August 2003 to June 2021 were grouped into LR or GA. Outcomes included ICU admission and prolonged hospital stay (>2 d). Procedures were stratified into groups of 2 y periods, and outcomes were analyzed within each time period. Univariable and multivariate analyses were used to assess outcomes. RESULTS: LR was associated with reduced ICU admissions (22.3% versus 32.1%, P < 0.001) and prolonged hospital stays (14.3% versus 7.9%, P < 0.001) overall. When stratified by year, LR maintained its association with reduced ICU admissions in 2014-2015 (21.8% versus 34.0%, P < 0.001), 2016-2017 (23.6% versus 31.6%, P < 0.001), 2018-2019 (18.5% versus 30.2%, P < 0.001), and 2020-2021 (15.8% versus 28.8%, P < 0.001), although this was highly facility dependent. LR was associated with fewer prolonged hospital stays in 2014-2015 (15.6% versus 20.4%, P = 0.001) and 2016-2017 (13.3% versus 16.6%, P = 0.006) but not after 2017. CONCLUSIONS: GA and LR have similar rates of prolonged hospital stays after 2017, while LR anesthesia was associated with reduced rates of ICU admissions, although this is facility-dependent, providing a potential avenue for resource preservation in patients suitable for LR.

Dysregulated Lymphocyte Antigen Receptor Signaling in Common Variable Immunodeficiency with Granulomatous Lymphocytic Interstitial Lung Disease.

PURPOSE: A subset of common variable immunodeficiency (CVID) patients either presents with or develops autoimmune and lymphoproliferative complications, such as granulomatous lymphocytic interstitial lung disease (GLILD), a major cause of morbidity and mortality in CVID. While a myriad of phenotypic lymphocyte derangements has been associated with and described in GLILD, defects in T and B cell antigen receptor (TCR/BCR) signaling in CVID and CVID with GLILD (CVID/GLILD) remain undefined, hindering discovery of biomarkers for disease monitoring, prognostic prediction, and personalized medicine approaches. METHODS: To identify perturbations of immune cell subsets and TCR/BCR signal transduction, we applied mass cytometry analysis to peripheral blood mononuclear cells (PBMCs) from healthy control participants (HC), CVID, and CVID/GLILD patients. RESULTS: Patients with CVID, regardless of GLILD status, had increased frequency of HLADR+CD4+ T cells, CD57+CD8+ T cells, and CD21lo B cells when compared to healthy controls. Within these cellular populations in CVID/GLILD patients only, engagement of T or B cell antigen receptors resulted in discordant downstream signaling responses compared to CVID. In CVID/GLILD patients, CD21lo B cells showed perturbed BCR-mediated phospholipase C gamma and extracellular signal-regulated kinase activation, while HLADR+CD4+ T cells and CD57+CD8+ T cells displayed disrupted TCR-mediated activation of kinases most proximal to the receptor. CONCLUSION: Both CVID and CVID/GLILD patients demonstrate an activated T and B cell phenotype compared to HC. However, only CVID/GLILD patients exhibit altered TCR/BCR signaling in the activated lymphocyte subsets. These findings contribute to our understanding of the mechanisms of immune dysregulation in CVID with GLILD.

Locoregional anesthesia is associated with reduced hospital stay and need for intensive care unit care of elective endovascular aneurysm repair patients in the Vascular Quality Initiative.

OBJECTIVE: It has been shown local or regional anesthetic techniques are a feasible alternative to general anesthesia for endovascular aortic aneurysm repair (EVAR). However, studies to date have shown controversial findings with respect to the benefit of locoregional anesthesia (LR) in the elective setting. The objective of this study is to compare postoperative outcomes between LR and general anesthesia (GA) in the setting of elective EVAR, using a large, multicenter database. METHODS: Using the Society for Vascular Surgery Vascular Quality Initiative database, we retrospectively analyzed all patients who underwent elective EVAR from August 2003 to June 2021. Patients were grouped by anesthetic type based on the level of consciousness afforded by the anesthetic: local or regional anesthesia (LR) vs GA. Primary outcomes were total postoperative hospital length-of-stay (LOS) and intensive care unit (ICU) LOS. Propensity score matching was used for risk adjustment and to analyze the primary outcomes with confirmatory analysis using logistic or linear regression, as appropriate, in single and multilevel models. Secondary outcomes were 30-day mortality, 1-year mortality, postoperative outcomes, operative time, fluoroscopy time, and reoperation rate. These were analyzed following propensity score matching as well as using logistic regression and Cox proportional hazard regression in single and multilevel models, as appropriate. RESULTS: A total of 50,809 patients underwent elective EVAR from 2003 to 2021. Of these, 4302 repairs used LR (8.5%) and 46,507 (91.5%) were performed under GA. After employing propensity score matching, two groups of 3027 patients were produced. These showed no significant difference in 30-day mortality (odds ratio, 1.22; P = .53), 1-year mortality (hazard ratio, 1.06; P = .62), or any postoperative outcomes. LR was found to be significantly associated with shorter hospital stays (≤2 days) (12.5% vs 14.8%; P = .01), decreased ICU utilization (19.3% vs 30.6%; P < .001), decreased operative time (110.8 vs 117.3 minutes; P < .001), decreased fluoroscopy time (21.0 vs 22.7 minutes; P < .001), and a slight reduction in reoperation rate (1.2% vs 1.9%; P = .02), which all remained significant following single-level and multilevel multivariate analyses accounting for hospital and physician random effects. CONCLUSIONS: These data suggest that LR anesthesia is safe and may offer advantages in reducing resource utilization for patients undergoing elective EVAR, primarily based on associations with reduced ICU care and reduced hospital stay. Given these findings, LR may prove an advantageous technique in appropriately selected patient populations.

Long-term anticoagulation is associated with type II endoleaks and failure of sac regression after endovascular aneurysm repair.

OBJECTIVE: Within the context of endovascular aneurysm repair (EVAR), the role of anticoagulation therapy on endoleak development and subsequent reintervention is unclear with conflicting data in the literature. The hypothesis of this study is that long-term anticoagulation is associated with persistent type II endoleaks and failure of sac regression in patients undergoing endoluminal repair of intact infrarenal aortic aneurysm. METHODS: Retrospective cohort abstracted from the Vascular Quality Initiative index hospitalization and long-term follow-up datasets for EVAR (2003-2017) were included in the analysis. Patients not taking aspirin preoperatively and postoperatively were excluded. Patients taking anticoagulation and aspirin concomitantly (treatment) after the index procedure were compared against patients taking aspirin alone (control). Anticoagulation included warfarin and novel oral anticoagulants, including factor Xa inhibitors and direct thrombin inhibitors. One-to-one greedy matching using propensity scores was implemented to match patients. The primary end points were failure of aneurysm sac regression, sac expansion, risk of endoleak, and reintervention rate for endoleak at follow-up. Sac regression was defined as a decrease of at least 5 mm and sac expansion was defined as an increase of at least 5 mm. RESULTS: There were 9004 patients who received ASA alone and 332 patients who received ASA and anticoagulation. Propensity scores were used to create 301 matching pairs to account for differences in baseline characteristics and comorbidities, including but not limited to age, sex, smoking, coronary artery disease, heart failure, and chronic kidney disease between the treatment and control groups. After adjusting for covariables anticoagulation use was independently associated with a significantly decreased abdominal aortic aneurysm sac regression (41.59% vs 58.41%; P = .001), but no statistically significant difference in sac expansion with long-term anticoagulation use (9.7% vs 4.9%; P = .056). There was increased risk of type II endoleaks (11.96% vs 6.31%; P = .023; relative risk, 1.89; 95% confidence interval, 1.11-3.23; P = .016), but no significant differences in type I, III, or indeterminate endoleaks. There was no statistical difference in 2-year reintervention rates (4.32% vs 2.66%; hazard ratio, 1.43; 95% confidence interval, 0.55-3.77; P = .461). There were no differences in any primary outcome between warfarin and novel oral anticoagulants. CONCLUSIONS: These data demonstrate that long-term aspirin plus anticoagulation use is associated with a lack of aortic sac reduction and persistent type II endoleak, but not an increased risk for subsequent reintervention. Because prior studies have demonstrated that sac regression is a correlate of survival, these findings associating regression failure suggest a potential therapeutic failure for patients undergoing EVAR who also require long-term anticoagulation therapy. Although not a contraindication, long-term anticoagulation should be considered when counseling patients with a surgical indication aortic aneurysm.

p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients.

Ovarian cancer is a lethal gynecological malignancy, and to improve survival, it is important to identify novel prognostic and therapeutic targets. In this study, we present a role for p21-activated kinase 4 (Pak4) in ovarian cancer progression. We show a significant association between increased expression of Pak4 and its activated form, phosphorylated (p)-Pak4 Ser(474), with metastasis of ovarian cancers, shorter overall and disease-free survival, advanced stage and high-grade cancers, serous/clear cell histological subtypes, and reduced chemosensitivity. Pak4 overexpression was also observed in ovarian cancer cell lines. Pak4 and p-Pak4 expression were detected both in the nucleus and cytoplasm of ovarian cancer cells, in vitro as well as in vivo. Stable knockdown of Pak4 in ovarian cancer cell lines led to reduced cell migration, invasion, and proliferation, along with reduced c-Src, ERK1/2, and epidermal growth factor receptor (EGFR) activation and decreased matrix metalloproteinase 2 (MMP2) expression. Conversely, Pak4 overexpression promoted ovarian cancer cell migration and invasion in a c-Src, MEK-1, MMP2, and kinase-dependent manner, and induced cell proliferation through the Pak4/c-Src/EGFR pathway that controls cyclin D1 and CDC25A expression. Stable knockdown of Pak4 also impeded tumor growth and dissemination in nude mice. This report reveals the association between Pak4 and important clinicopathologic parameters, suggesting Pak4 to be a significant prognostic marker and potential therapeutic molecular target in ovarian cancer. The implied possible cross-talk between Pak4 and EGFR suggests the potential of dual targeting of EGFR and Pak4 as a unique therapeutic approach for cancer therapy.

Intermediate pressure-normalized principal wall strain values are associated with increased abdominal aortic aneurysmal growth rates.

Introduction: Current abdominal aortic aneurysm (AAA) assessment relies on analysis of AAA diameter and growth rate. However, evidence demonstrates that AAA pathology varies among patients and morphometric analysis alone is insufficient to precisely predict individual rupture risk. Biomechanical parameters, such as pressure-normalized AAA principal wall strain (ερ+¯/PP, %/mmHg), can provide useful information for AAA assessment. Therefore, this study utilized a previously validated ultrasound elastography (USE) technique to correlate ερ+¯/PP with the current AAA assessment methods of maximal diameter and growth rate. Methods: Our USE algorithm utilizes a finite element mesh, overlaid a 2D cross-sectional view of the user-defined AAA wall, at the location of maximum diameter, to track two-dimensional, frame-to-frame displacements over a full cardiac cycle, using a custom image registration algorithm to produce ερ+¯/PP. This metric was compared between patients with healthy aortas and AAAs (≥3 cm) and compared between small and large AAAs (≥5 cm). AAAs were then separated into terciles based on ερ+¯/PP values to further assess differences in our metric across maximal diameter and prospective growth rate. Non-parametric tests of hypotheses were used to assess statistical significance as appropriate. Results: USE analysis was conducted on 129 patients, 16 healthy aortas and 113 AAAs, of which 86 were classified as small AAAs and 27 as large. Non-aneurysmal aortas showed higher ερ+¯/PP compared to AAAs (0.044 ± 0.015 vs. 0.034 ± 0.017%/mmHg, p = 0.01) indicating AAA walls to be stiffer. Small and large AAAs showed no difference in ερ+¯/PP. When divided into terciles based on ερ+¯/PP cutoffs of 0.0251 and 0.038%/mmHg, there was no difference in AAA diameter. There was a statistically significant difference in prospective growth rate between the intermediate tercile and the outer two terciles (1.46 ± 2.48 vs. 3.59 ± 3.83 vs. 1.78 ± 1.64 mm/yr, p = 0.014). Discussion: There was no correlation between AAA diameter and ερ+¯/PP, indicating biomechanical markers of AAA pathology are likely independent of diameter. AAAs in the intermediate tercile of ερ+¯/PP values were found to have nearly double the growth rates than the highest or lowest tercile, indicating an intermediate range of ερ+¯/PP values for which patients are at risk for increased AAA expansion, likely necessitating more frequent imaging follow-up.

Expansion of extrafollicular B and T cell subsets in childhood-onset systemic lupus erythematosus.

Introduction: Most childhood-onset SLE patients (cSLE) develop lupus nephritis (cLN), but only a small proportion achieve complete response to current therapies. The prognosis of children with LN and end-stage renal disease is particularly dire. Mortality rates within the first five years of renal replacement therapy may reach 22%. Thus, there is urgent need to decipher and target immune mechanisms that drive cLN. Despite the clear role of autoantibody production in SLE, targeted B cell therapies such as rituximab (anti-CD20) and belimumab (anti-BAFF) have shown only modest efficacy in cLN. While many studies have linked dysregulation of germinal center formation to SLE pathogenesis, other work supports a role for extrafollicular B cell activation in generation of pathogenic antibody secreting cells. However, whether extrafollicular B cell subsets and their T cell collaborators play a role in specific organ involvement in cLN and/or track with disease activity remains unknown. Methods: We analyzed high-dimensional mass cytometry and gene expression data from 24 treatment naïve cSLE patients at the time of diagnosis and longitudinally, applying novel computational tools to identify abnormalities associated with clinical manifestations (cLN) and disease activity (SLEDAI). Results: cSLE patients have an extrafollicular B cell expansion signature, with increased frequency of i) DN2, ii) Bnd2, iii) plasmablasts, and iv) peripheral T helper cells. Most importantly, we discovered that this extrafollicular signature correlates with disease activity in cLN, supporting extrafollicular T/B interactions as a mechanism underlying pediatric renal pathogenesis. Discussion: This study integrates established and emerging themes of extrafollicular B cell involvement in SLE by providing evidence for extrafollicular B and peripheral T helper cell expansion, along with elevated type 1 IFN activation, in a homogeneous cohort of treatment-naïve cSLE patients, a point at which they should display the most extreme state of their immune dysregulation.

p21-Activated kinase-1 promotes aggressive phenotype, cell proliferation, and invasion in gestational trophoblastic disease.

Gestational trophoblastic disease (GTD) includes hydatidiform mole (HM), which can develop persistent gestational trophoblastic neoplasia requiring chemotherapy; choriocarcinoma, which is a frankly malignant tumor; placental site trophoblastic tumor; and epithelioid trophoblastic tumor. p21-Activated kinases (PAKs) promote malignant tumor progression. Therefore, this study investigated PAK1, PAK2, and p-PAK2 Ser(20) in the pathogenesis of GTD. By real-time PCR, PAK1 mRNA was significantly higher in HMs, particularly metastatic HMs (P = 0.046) and HMs that developed persistent disease (P = 0.011), when compared with normal placentas. By immunohistochemistry, significantly increased cytoplasmic PAK1 immunoreactivity in cytotrophoblasts was also detected in HMs (P = 0.042) and choriocarcinomas (P = 0.003). In addition, HMs that developed persistent disease displayed higher PAK1 immunoreactivity than those that regressed (P = 0.016), and elevated PAK1 immunoreactivity was observed in placental site trophoblastic tumors. Indeed, there was significant positive correlation between PAK1 expression and the proliferative indices Ki-67 (P = 0.016) and MCM7 (P = 0.026). Moreover, higher PAK1 mRNA and protein expression was confirmed in the choriocarcinoma cell-lines JEG-3 and JAR; however, PAK2 mRNA and p-PAK2 immunoreactivity showed a similar expression pattern in normal first trimester placentas and GTD. Knockdown of PAK1 in JEG-3 and JAR reduced cell proliferation, migration, and invasion ability, up-regulated p16, and down-regulated vascular endothelial growth factor and MT1-MMP expression. This is the first report revealing the involvement of PAK1 in the pathogenesis and clinical progress of GTD.

Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion.

Ovarian cancer is a gynecological malignancy with high mortality. Therefore, the identification of novel prognostic and therapeutic targets is important. p21-activated kinases (Paks) are involved in cytoskeleton reorganization. This study investigated the clinical significance of total and phosphorylated (p) Pak1 and Pak2 as well as their functional roles in ovarian cancer. Expressions of Pak1, p-Pak1 Thr(212), Pak2 and p-Pak2 Ser(20) in ovarian normal and cancerous cell lines as well as in clinical samples of ovarian tumors were evaluated. The effects of Pak1 and Pak2 on ovarian cancer cell functions were determined. Pak1, p-Pak1 and p-Pak2 were overexpressed in ovarian cancer cell lines, and clinical samples of ovarian cancers were compared with benign ovarian lesions/inclusion cysts. Similar Pak2 expression levels were observed among normal and cancerous cell lines and clinical samples. After multiple testing correction, high Pak1 and nuclear p-Pak1 expression in ovarian cancers was significantly associated with histological type and tumor grade, respectively. Pak1 and p-Pak1 expression was associated with poor overall and disease-free survival. Pak1 was an independent prognostic factor. Knockdown of Pak1 and Pak2 in ovarian cancer cell lines reduced cell migration and invasion but did not affect cell proliferation and apoptosis. Knockdown of Pak1 also reduced p38 activation and downregulated vascular endothelial growth factor. Conversely, ectopic Pak1 overexpression enhanced ovarian cancer cell migration and invasion in a kinase-dependent manner, along with increased p38 activation. Our findings suggest that Pak1, p-Pak1 and p-Pak2 play important roles in ovarian carcinogenesis. Pak1 and p-Pak1 may be potential prognostic markers and therapeutic molecular targets in ovarian cancer.

CTLA4 Message Reflects Pathway Disruption in Monogenic Disorders and Under Therapeutic Blockade.

CTLA-4 is essential for immune tolerance. Heterozygous CTLA4 mutations cause immune dysregulation evident in defective regulatory T cells with low levels of CTLA-4 expression. Biallelic mutations in LRBA also result in immune dysregulation with low levels of CTLA-4 and clinical presentation indistinguishable from CTLA-4 haploinsufficiency. CTLA-4 has become an immunotherapy target whereby its blockade with a monoclonal antibody has resulted in improved survival in advanced melanoma patients, amongst other malignancies. However, this therapeutic manipulation can result in autoimmune/inflammatory complications reminiscent of those seen in genetic defects affecting the CTLA-4 pathway. Despite efforts made to understand and establish disease genotype/phenotype correlations in CTLA-4-haploinsufficiency and LRBA-deficiency, such relationships remain elusive. There is currently no specific immunological marker to assess the degree of CTLA-4 pathway disruption or its relationship with clinical manifestations. Here we compare three different patient groups with disturbances in the CTLA-4 pathway-CTLA-4-haploinsufficiency, LRBA-deficiency, and ipilimumab-treated melanoma patients. Assessment of CTLA4 mRNA expression in these patient groups demonstrated an inverse correlation between the CTLA4 message and degree of CTLA-4 pathway disruption. CTLA4 mRNA levels from melanoma patients under therapeutic CTLA-4 blockade (ipilimumab) were increased compared to patients with either CTLA4 or LRBA mutations that were clinically stable with abatacept treatment. In summary, we show that increased CTLA4 mRNA levels correlate with the degree of CTLA-4 pathway disruption, suggesting that CTLA4 mRNA levels may be a quantifiable surrogate for altered CTLA-4 expression.

A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation.

The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rß, and IL-2Rγ subunits, with defects in IL-2Rα and IL-2Rγ and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rß, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2Rß surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rß-/- animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56bright subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rß expression and signaling in T and NK cells.

Single-cell Analysis of Immunophenotype and Cytokine Production in Peripheral Whole Blood via Mass Cytometry.

Cytokines play a pivotal role in the pathogenesis of autoimmune diseases. Hence, the measurement of cytokine levels has been the focus of multiple studies in an attempt to understand the precise mechanisms that lead to the breakdown of self-tolerance and subsequent autoimmunity. Approaches thus far have been based on the study of one specific aspect of the immune system (a single or few cell types or cytokines), and do not offer a global assessment of complex autoimmune disease. While patient sera-based studies have afforded important insights into autoimmunity, they do not provide the specific cellular source of the dysregulated cytokines detected. A comprehensive single-cell approach to evaluate cytokine production in multiple immune cell subsets, within the context of "intrinsic" patient-specific plasma circulating factors, is described here. This approach enables monitoring of the patient-specific immune phenotype (surface markers) and function (cytokines), either in its native "intrinsic pathogenic" disease state, or in the presence of therapeutic agents (in vivo or ex vivo).

p21-Activated Kinases 1, 2 and 4 in Endometrial Cancers: Effects on Clinical Outcomes and Cell Proliferation.

p21-activated kinases (Paks) are serine/threonine protein kinases involved in biological events linked to malignant tumor progression. In this study, expression of Pak1, p-Pak2 Ser20, Pak4, pPak4 Ser474 in 21 normal endometrium, 16 hyperplastic endometrium without atypia, 17 atypical complex hyperplasia and 67 endometrial cancers was assessed by immunohistochemistry and correlated with clinicopathological parameters. We also accessed the proliferative role and downstream targets of Pak1 in endometrial cancer. Pak1 was expressed in cytoplasm whereas Pak4 and p-Pak4 were expressed in both cytoplasm and nucleus of endometrial tissues. In normal endometrium, significantly higher Pak1 (P = 0.028) and cytoplasmic p-Pak2 (P = 0.048) expression was detected in proliferative endometrium than secretory endometrium. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 was significantly overexpressed in endometrial cancer when compared to atrophic endometrium (all P<0.05). Moreover, type I endometrioid carcinomas showed significantly higher Pak1 expression than type II non-endometrioid carcinomas (P<0.001). On the other hand, Pak1, Pak4 and p-Pak4 expression negatively correlated with histological grade (all P<0.05) while p-Pak2 and cytoplasmic Pak4 expression inversely correlated with myometrial invasion (all P<0.05). Furthermore, patients with endometrial cancers with lower cytoplasmic Pak4 expression showed poorer survival (P = 0.026). Multivariate analysis showed cytoplasmic Pak4 is an independent prognostic factor. Functionally, knockdown of Pak1, but not Pak4, in endometrial cancer cell line led to reduced cell proliferation along with reduced cyclin D1, estrogen receptor (ERα) and progestogen receptor (PR) expression. Significant correlation between Pak1 and PR expression was also detected in clinical samples. Our findings suggest that Pak1 and cytoplasmic p-Pak2 may promote cell proliferation in normal endometrium during menstral cycle. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 are involved in the pathogenesis of endometrial cancer especially in postmenopausal women. Pak1 promote endometrial cancer cell proliferation, particular in type I endometrioid carcinoma. Cytoplasmic Pak4 can be potential prognostic marker in endometrial cancer.

Paradoxical impact of two folate receptors, FRα and RFC, in ovarian cancer: effect on cell proliferation, invasion and clinical outcome.

Despite being an essential vitamin, folate has been implicated to enhance tumor growth, as evidenced by reports on overexpression of folate receptor alpha (FRα) in carcinomas. The role of another folate transporter, reduced folate carrier (RFC), is largely unknown. This study investigated the roles of folate, FRα and RFC in ovarian cancers. We demonstrated FRα mRNA and protein overexpression and reduced RFC expression in association with FRα gene amplification and RFC promoter hypermethylation, respectively. FRα overexpression was associated with tumor progression while RFC expression incurred a favorable clinical outcome. Such reciprocal expression pattern was also observed in ovarian cancer cell lines. Folate was shown to promote cancer cell proliferation, migration and invasion in vitro, and down-regulate E-cadherin expression. This effect was blocked after either stable knockdown of FRα or ectopic overexpression of RFC. This hitherto unreported phenomenon suggests that, RFC can serve as a balancing partner of FRα and confer a protective effect in patients with high FRα-expressing ovarian carcinomas, as evidenced by their prolonged overall and disease-free survivals. In conclusion, we report on the paradoxical impact of FRα (putative oncogenic) and RFC (putative tumor suppressive) in human malignancies. FRα and RFC may potentially be explored as therapeutic target or prognostic marker respectively. We recommend caution and additional research on folate supplements in cancer patients.