The Schistosoma mansoni nuclear receptor FTZ-F1 maintains esophageal gland function via transcriptional regulation of meg-8.3.

Schistosomes infect over 200 million of the world's poorest people, but unfortunately treatment relies on a single drug. Nuclear hormone receptors are ligand-activated transcription factors that regulate diverse processes in metazoans, yet few have been functionally characterized in schistosomes. During a systematic analysis of nuclear receptor function, we found that an FTZ-F1-like receptor was essential for parasite survival. Using a combination of transcriptional profiling and chromatin immunoprecipitation (ChIP), we discovered that the micro-exon gene meg-8.3 is a transcriptional target of SmFTZ-F1. We found that both Smftz-f1 and meg-8.3 are required for esophageal gland maintenance as well as integrity of the worm's head. Together, these studies define a new role for micro-exon gene function in the parasite and suggest that factors associated with the esophageal gland could represent viable therapeutic targets.

Fifteen-minute consultation: Bruising in the premobile child.

A bruise in a premobile infant is an uncommon finding and often results in referral to the paediatric or emergency departments, acknowledging the potential for physical abuse in this vulnerable cohort. Our role as clinicians is to undertake a thorough assessment, consider potential differentials and organise appropriate investigations, with involvement of the wider multidisciplinary team. In this article, we use a case vignette to discuss how one would approach a bruise in the premobile infant including the evidence base.

Anticoagulation Strategies in Pediatric Cardiopulmonary Bypass, Weight-Based vs. Concentration-Based Approaches.

Pediatric patients undergoing cardiopulmonary bypass (CPB) require adequate anticoagulation to combat hemostatic activation. Heparin is used to bind and catalyze antithrombin III (ATIII) that works to inhibit clot formation. To dose heparin, a weight-based (WB) or patient-specific concentration-based (PSCB) method can be used. The WB protocol calculates the dose based on the patients' weight and uses an activated clotting time (ACT) test to ensure anticoagulation. The ACT has limitations during CPB especially for pediatric patients who have immature hemostatic systems. The PSCB method predicts the patients' response to heparin by projecting a heparin dose-response (HDR) curve. Some investigators have found benefit to using the PSCB method but further investigation into how well the HDR predicts the heparin response is needed. A literature review was conducted for studies that looked at heparin management strategies in pediatric CPB patients between 1992 and 2020. Articles that focused on pediatric physiology, heparin management strategies, and anticoagulation were included. Articles older than 1990 were excluded. The literature review highlights that utilizing the PSCB approach more adequately anticoagulated patients. The WB protocol was found to have several flaws due to its reliance on the ACT, especially in infants. The results show that further investigation is needed to understand why there is benefit to using the PSCB approach. Observing the association between the HDR curve and subsequent heparin concentrations could determine how accurately it predicts the patients' response to heparin and why there is benefit to using this method.

Fifteen-minute consultation: Apparent vaginal bleeding in the pre-pubertal girl.

A parent or carer's observation of blood in a child's nappy or underwear can be quite alarming for both parent and child and may indicate vaginal bleeding. At first glance, it may be difficult to ascertain whether the bleeding is from the skin, genital tract, urinary tract or anus. Confirmed vaginal bleeding in a pre-pubertal girl is rare but always abnormal and requires comprehensive assessment to determine the cause. Recognition of normal female pre-pubertal anatomy is essential to detect any abnormalities. Appropriate action should be taken according to findings on initial inspection of the ano-genital area. The possibility of child sexual abuse and the need for specialist paediatric sexual offences medicine examination by an FME (Forensic Medical Examiner) or specialist paediatrician should always be considered. This article offers a systematic approach to assessment in pre-pubertal girls with apparent vaginal bleeding which will benefit general paediatricians, emergency department practitioners and GPs.

Phase I Trial of a Modified Vaccinia Ankara Priming Vaccine Followed by a Fowlpox Virus Boosting Vaccine Modified to Express Brachyury and Costimulatory Molecules in Advanced Solid Tumors.

LESSONS LEARNED: Modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury followed by fowlpox virus-BN-Brachyury was well tolerated upon administration to patients with advanced cancer. Sixty-three percent of patients developed CD4+ and/or CD8+ T-cell responses to brachyury after vaccination. BN-Brachyury vaccine also induced T-cell responses against CEA and MUC1, which are cascade antigens, that is, antigens not encoded in the vaccines. BACKGROUND: Brachyury, a transcription factor, plays an integral role in the epithelial-mesenchymal transition, metastasis, and tumor resistance to chemotherapy. It is expressed in many tumor types, and rarely in normal tissues, making it an ideal immunologic target. Bavarian Nordic (BN)-Brachyury consists of vaccination with modified vaccinia Ankara (MVA) priming followed by fowlpox virus (FPV) boosting, each encoding transgenes for brachyury and costimulatory molecules. METHODS: Patients with metastatic solid tumors were treated with two monthly doses of MVA-brachyury s.c., 8 × 108 infectious units (IU), followed by FPV-brachyury s.c., 1 × 109 IU, for six monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability. RESULTS: Eleven patients were enrolled from March 2018 to July 2018 (one patient was nonevaluable). No dose-limiting toxicities were observed. The most common treatment-related adverse event was grade 1/2 injection-site reaction observed in all patients. Best overall response was stable disease in six patients, and the 6-month progression-free survival rate was 50%. T cells against brachyury and cascade antigens CEA and MUC1 were detected in the majority of patients. CONCLUSION: BN-Brachyury vaccine is well tolerated and induces immune responses to brachyury and cascade antigens and demonstrates some evidence of clinical benefit.

Management of breast cancer risk in BRCA1/2 mutation carriers who are unaffected with cancer.

Pathogenic mutations in BRCA1 and BRCA2 genes markedly increase the risk of breast cancer and other cancers such as ovarian/fallopian tube, pancreatic, prostate, and melanoma. Patients with BRCA1 mutations have a slightly higher lifetime risk of breast cancer than BRCA2 mutation carriers, and both BRCA1 and BRCA2 carriers tend to develop breast cancer at an earlier age than the general population. In this review, we will discuss management recommendations to reduce breast cancer risk for BRCA1/2 mutation carriers including special populations of carriers such as pregnant or lactating patients and men. Breast cancer screening, including clinical breast examination, mammogram, and breast MRI, is important for detecting breast cancer at an early and likely curable stage. In addition to screening, counseling on risk-reducing surgeries is strongly recommended for BRCA1/2 carriers. Risk-reducing mastectomy decreases the risk of breast cancer development, and risk-reducing salpingo-oophorectomy decreases ovarian cancer-specific as well as overall mortality, but controversy exists regarding its impact on breast cancer-specific mortality. Given the effectiveness of screening for breast cancer, further management should be carried out on an individual basis taking into account quality of life and psychosocial factors, and recommendations should be readdressed periodically as science progresses and patients' goals may change.

Epidemiology of adolescent trauma in England: a review of TARN data 2008-2017.

OBJECTIVES: Trauma contributes significantly to adolescent morbidity and mortality. We aimed to ascertain the epidemiology of adolescent trauma to inform prevention strategies. METHODS: Data were abstracted from TARN (Trauma Audit Research Network) from English sites over a 10-year period (2008-2017). Adolescents were defined as 10-24 completed years. Descriptive statistical analysis was used in this study. RESULTS: There were 40 680 recorded cases of adolescent trauma. The majority were male (77.3%) and aged 16-24 years old (80.5%). There was a 2.6-fold increase during the study time frame (p<0.0001) in the total annual number of cases reported to TARN. To account for increasing hospital participation, the unit trauma cases per hospital per year was used, noting an increasing trend (p=0.048). Road traffic collision (RTC) was the leading cause of adolescent trauma (50.3%). Pedestrians (41.2%) and cyclists (32.6%) were more prevalent in the 10-15 year group, while drivers (22.9%) and passengers (17.8%) predominated in the 16-24 year group. Intentional injury was reported in 20.7% (alleged assault in 17.2% and suspected self-harm in 3.5%). This was more prevalent in the 16-24 year group. The proportion of trauma reported due to violence has increased with stabbings increasing from 6.9% in 2008 to 10.2% in 2017 (p<0.0001). Evidence of alcohol or drug use was recorded in 20.1% of cases. There was an increase in the number treated in major trauma centres (45.7% 2008 vs 63.5% 2017, p<0.0001). Trauma was more likely to occur between 08:00 and 00:00, at weekends and between April and October. Overall mortality rate was 4.1%. Those with a known psychiatric diagnosis had a higher mortality (6.3% vs 4.4%, p<0.001). CONCLUSIONS: RTCs and intentional injuries are leading aetiologies. Healthcare professionals and policy-makers need to prioritise national preventative public health measures and early interventions to reduce the incidence of trauma in this vulnerable age group.

Evaluation of the early warning, alert and response system after Cyclone Winston, Fiji, 2016.

OBJECTIVE: To assess the performance of an early warning, alert and response system (EWARS) developed by the World Health Organization (WHO) - EWARS in a Box - that was used to detect and control disease outbreaks after Cyclone Winston caused destruction in Fiji on 20 February 2016. METHODS: Immediately after the cyclone, Fiji's Ministry of Health and Medical Services, supported by WHO, started to implement EWARS in a Box, which is a smartphone-based, automated, early warning surveillance system for rapid deployment during health emergencies. Both indicator-based and event-based surveillance were employed. The performance of the system between 7 March and 29 May 2016 was evaluated. Users' experience with the system was assessed in interviews using a semi-structured questionnaire and by a cross-sectional survey. The system's performance was assessed using data from the EWARS database. FINDINGS: Indicator-based surveillance recorded 34 113 cases of the nine syndromes under surveillance among 326 861 consultations. Three confirmed outbreaks were detected, and no large outbreak was missed. Users were satisfied with the performance of EWARS and judged it useful for timely monitoring of disease trends and outbreak detection. The system was simple, stable and flexible and could be rapidly deployed during a health emergency. The automated collation, analysis and dissemination of data reduced the burden on surveillance teams, saved human resources, minimized human error and ensured teams could focus on public health responses. CONCLUSION: In Fiji, EWARS in a Box was effective in strengthening disease surveillance during a national emergency and was well regarded by users.

Tissue Degeneration following Loss of Schistosoma mansoni cbp1 Is Associated with Increased Stem Cell Proliferation and Parasite Death In Vivo.

Schistosomiasis is second only to malaria in terms of the global impact among diseases caused by parasites. A striking feature of schistosomes are their ability to thrive in their hosts for decades. We have previously demonstrated that stem cells, called neoblasts, promote homeostatic tissue maintenance in adult schistosomes and suggested these cells likely contribute to parasite longevity. Whether these schistosome neoblasts have functions independent of homeostatic tissue maintenance, for example in processes such as tissue regeneration following injury, remains unexplored. Here we characterize the schistosome CBP/p300 homolog, Sm-cbp1. We found that depleting cbp1 transcript levels with RNA interference (RNAi) resulted in increased neoblast proliferation and cell death, eventually leading to organ degeneration. Based on these observations we speculated this increased rate of neoblast proliferation may be a response to mitigate tissue damage due to increased cell death. Therefore, we tested if mechanical injury was sufficient to stimulate neoblast proliferation. We found that mechanical injury induced both cell death and neoblast proliferation at wound sites, suggesting that schistosome neoblasts are capable of mounting proliferative responses to injury. Furthermore, we observed that the health of cbp1(RNAi) parasites progressively declined during the course of our in vitro experiments. To determine the fate of cbp1(RNAi) parasites in the context of a mammalian host, we coupled RNAi with an established technique to transplant schistosomes into the mesenteric veins of uninfected mice. We found transplanted cbp1(RNAi) parasites were cleared from vasculature of recipient mice and were incapable of inducing measurable pathology in their recipient hosts. Together our data suggest that injury is sufficient to induce neoblast proliferation and that cbp1 is essential for parasite survival in vivo. These studies present a new methodology to study schistosome gene function in vivo and highlight a potential role for schistosome neoblasts in promoting tissue repair following injury.

Aplasia Cutis Congenita with Ischemic Cortical Change and Normal Array Cytogenetic Analysis with a Fetus Papyraceus Twin.

BACKGROUND: Aplasia cutis congenita (ACC) is a heterogeneous condition that can be associated with fetus papyraceus. Few reports exist documenting genetic investigations in ACC or determining the etiology and recurrence risks. OBJECTIVE: We present a Frieden group 5 ACC with fetus papyraceus along with molecular studies. RESULTS: The newborn had multifocal aplasia cutis congenita involving the head, trunk, and limbs with cerebral ischemic changes demonstrated by imaging. The newborn had a monochorionic twin fetus papyraceus. The array cytogenetic analysis was normal. CONCLUSION: Supported by the ischemic cerebral damage, a monochorionic twin fetus papyraceus (monochorionic twins often have vascular anastomoses), and a normal cytogenetic array, this ACC with Frieden group 5 may have resulted from rapid but non-fatal exsanguination of the surviving twin into the dead twin. This type of ACC may have a low recurrence risk.

Reduction in Cell Viability and in Homeobox Protein Levels Following in Vitro Exposure to δ-tocopherol in Acute Myeloid Leukemia.

δ-Tocopherol (δ-T), the least prevalent tocopherol in our diet, was described to have a more potent anticancer activity in solid tumors compared to the other tocopherols. δ-T induces tumor cell death through peroxisome proliferator-activated receptor γ (PPAR-γ) induction, cyclin-D1 inhibition, and modulation of redox balance. Nevertheless, the role of δ-T in preventing or treating hematologic malignancies has not been studied. In this study, we screened the efficacy of δ-T against six cell lines representing a wide spectrum of hematologic malignancies: Jurkat (acute T-cell leukemia), K-562 (chronic myeloid leukemia), KG-1 [acute myeloid leukemia (AML)], THP-1 (acute monocytic leukemia), TOM-1 (acute lymphoblastic leukemia), and UMCL01-101 (AIDS-associated diffuse large B-cell lymphoma). Interestingly, the AML cell line KG-1 was the only one to be significantly affected at concentrations of δ-T as low as 20 µM. The antileukemic activity of δ-T in AML was verified in a set of primary cells collected from patients newly diagnosed with AML. Apoptotic induction and cell cycle arrest explained the efficacy of δ-T against KG-1 cells. The mechanism of cell growth inhibition of δ-T was through downregulation of cyclin-D1 and a set of homeobox proteins (HOXA9, PBX1, and Cdx2) that have a well-documented role in the pathobiology of AML.

Inhibition of polyphosphate as a novel strategy for preventing thrombosis and inflammation.

Inorganic polyphosphates are linear polymers of orthophosphate that modulate blood clotting and inflammation. Polyphosphate accumulates in infectious microorganisms and is secreted by activated platelets; long-chain polyphosphate in particular is an extremely potent initiator of the contact pathway, a limb of the clotting cascade important for thrombosis but dispensable for hemostasis. Polyphosphate inhibitors therefore might act as novel antithrombotic/anti-inflammatory agents with reduced bleeding side effects. Antipolyphosphate antibodies are unlikely because of polyphosphate's ubiquity and simple structure; and although phosphatases such as alkaline phosphatase can digest polyphosphate, they take time and may degrade other biologically active molecules. We now identify a panel of polyphosphate inhibitors, including cationic proteins, polymers, and small molecules, and report their effectiveness in vitro and in vivo. We also compare their effectiveness against the procoagulant activity of RNA. Polyphosphate inhibitors were antithrombotic in mouse models of venous and arterial thrombosis and blocked the inflammatory effect of polyphosphate injected intradermally in mice. This study provides proof of principle for polyphosphate inhibitors as antithrombotic/anti-inflammatory agents in vitro and in vivo, with a novel mode of action compared with conventional anticoagulants.

Effect of echo-sampling strategy on the accuracy of out-of-phase and in-phase multiecho gradient-echo MRI hepatic fat fraction estimation.

PURPOSE: To assess the effect of echo-sampling strategy on the accuracy of out-of-phase (OP) and in-phase (IP) multiecho gradient-echo magnetic resonance imaging (MRI) hepatic fat fraction (FF) estimation, using MR spectroscopy (MRS) proton density FF (PDFF) as a reference standard. MATERIALS AND METHODS: In this Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant prospective study, 84 subjects underwent proton MRS and non-T1 -weighted gradient-echo imaging of the liver at 3T. Imaging data were collected at 16 nominally OP and IP echo times (TEs). MRI-FF was estimated while varying two echo-sampling parameters (number of consecutive echoes, starting echo number). For each combination of these parameters, MRI-FF estimation accuracy was assessed with slope, intercept, average bias, and R2 from a linear regression of MRS-PDFF on MRI-FF. The relationship between accuracy metrics and echo-sampling parameters was assessed by Spearman rank correlation. RESULTS: For FF calculations using 3-16 echoes and a starting echo number of 1, the intercept ranged from 0.0046 to 0.0124, slope from 0.941 to 0.96, average bias from 0.0034 to 0.0078, and R2 from 0.968 to 0.976. All four accuracy metrics were the best with the 3- and 4-echo calculations and worsened progressively with an increasing number of echoes. For a given number of echoes, there was an overall trend toward decreasing accuracy as starting echo number increased. Spearman correlation coefficients between starting echo number and intercept, slope, average bias, and R2 were 0.911, -0.64, -0.889, and -0.954, respectively, indicating progressive loss of accuracy in each case. CONCLUSION: Multiecho OP and IP imaging provided high FF estimation accuracy. Accuracy was highest using the earliest 3 or 4 echoes. Incorporation of additional echoes or delaying the starting echo number progressively reduced accuracy.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Bis{[2,2'-(5,8,11-tri-thia-2,14-di-aza-penta-deca-1,14-diene-1,15-di-yl)diphenolato]palladium(II)} aceto-nitrile monosolvate.

The asymmetric unit of the title compound, [Pd(C22H26N2O2S3)]2·CH3CN, contains two complex mol-ecules and a single uncoordinated lattice aceto-nitrile solvent mol-ecule. The Pd(II) cations have a trans-N2O2 square-planar geometry and the superposition of the two crystallographically independent Pd(II) complexes yields an overall r.m.s. deviation of 0.292 Å. The Pd⋯Pd separation in the asymmetric unit is 3.3776 (3) Å, while the PdN2O2 plane-plane fold angle is 1.62 (7)°. A short inter-molecular S⋯S contact between the central S atom of one complex and its inversion-related symmetry equivalent of 3.663 (2) Šis observed. Part of the ligand chain (S-C-C-S) in each complex mol-ecule is disordered over two orientations and refined occupancies that converged to 0.450 (10) and 0.550 (10) for the one complex mol-ecule, and 0.789 (9) and 0.211 (9) for the other.

A phase I trial of palbociclib and bosutinib with fulvestrant in patients with metastatic hormone receptor positive and HER2 negative (HR+ HER2-) breast cancer refractory to an aromatase inhibitor and a CDK4/6 inhibitor.

Standard treatment for metastatic hormone positive (HR+) breast cancer includes a combination of a CDK4/6 inhibitor and antiestrogen therapy. Despite durable responses, eventual endocrine resistance results in disease progression. The Src/Abl pathway has been shown to mediate endocrine resistance in breast cancer, thus providing a promising target for novel therapies. Bosutinib is a tyrosine kinase inhibitor that targets the Src/Abl pathway, which has been studied in hematologic malignancies. Preclinical data suggests that the addition of bosutinib to a CDK4/6 inhibitor and antiestrogen therapy has the potential to reverse endocrine resistance. This is a phase I, single arm, open-label clinical trial in which we evaluate the combination of palbociclib and fulvestrant with bosutinib in metastatic HR+ breast cancer. Patients with confirmed advanced HR+/HER2- breast cancer who have received no more than three lines of chemotherapy and have progressed on at least one aromatase inhibitor and one CDK4/6 inhibitor will be enrolled. Participants will be given a combination of palbociclib, fulvestrant and bosutinib over 28-day cycles. The primary objective of this study is to assess the safety and tolerability of bosutinib in combination with palbociclib and fulvestrant in the study population. Secondary objectives are to 1) determine the anti-tumor effect of this therapeutic combination by assessing overall response rate (ORR) and clinical benefit rate (CBR) after 6 months of treatment, 2) to determine the clinical pharmacology parameters of bosutinib in this regimen, and 3) to build a tissue repository at Georgetown Lombardi Comprehensive Cancer Center for further translational study.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints include the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) was associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Noninvasive classification of hepatic fibrosis based on texture parameters from double contrast-enhanced magnetic resonance images.

PURPOSE: To demonstrate a proof of concept that quantitative texture feature analysis of double contrast-enhanced magnetic resonance imaging (MRI) can classify fibrosis noninvasively, using histology as a reference standard. MATERIALS AND METHODS: A Health Insurance Portability and Accountability Act (HIPAA)-compliant Institutional Review Board (IRB)-approved retrospective study of 68 patients with diffuse liver disease was performed at a tertiary liver center. All patients underwent double contrast-enhanced MRI, with histopathology-based staging of fibrosis obtained within 12 months of imaging. The MaZda software program was used to compute 279 texture parameters for each image. A statistical regularization technique, generalized linear model (GLM)-path, was used to develop a model based on texture features for dichotomous classification of fibrosis category (F ≤2 vs. F ≥3) of the 68 patients, with histology as the reference standard. The model's performance was assessed and cross-validated. There was no additional validation performed on an independent cohort. RESULTS: Cross-validated sensitivity, specificity, and total accuracy of the texture feature model in classifying fibrosis were 91.9%, 83.9%, and 88.2%, respectively. CONCLUSION: This study shows proof of concept that accurate, noninvasive classification of liver fibrosis is possible by applying quantitative texture analysis to double contrast-enhanced MRI. Further studies are needed in independent cohorts of subjects.

Distinct roles of adenylyl cyclase VII in regulating the immune responses in mice.

The second messenger cAMP plays a critical role in regulating immune responses. Although well known for its immunosuppressive effect, cAMP is also required for the development of optimal immune responses. Thus, the regulation of this second messenger needs to be finely tuned and well balanced in a context dependent manner. To further understand the role of cAMP synthesis in the functions of the immune system, we focus on a specific adenylyl cyclase (AC) isoform, AC VII (AC7), which is highly expressed in the immune system. We show that mice deficient of AC7 are hypersensitive to LPS-induced endotoxic shock. Macrophages from AC7-deficient mice produce more of the proinflammatory cytokine, TNF-alpha, in response to LPS. The inability to generate intracellular cAMP response to serum factors, such as lysophosphatidic acid, is a potential cause for this phenotype. Thus, AC7 functions to control the extent of immune responses toward bacterial infection. However, it is also required for the optimal functions of B and T cells during adaptive immune responses. AC7 is the major isoform that regulates cAMP synthesis in both B and T cells. AC7-deficient mice display compromised Ab responses toward both T cell-independent and T cell-dependent Ags. The generation of memory T cells is also reduced. These results are the first to ascribe specific functions to an AC isoform in the immune system and emphasize the importance of cAMP synthesis by this isoform in shaping the immune responses.

Correction: MiR-277/4989 regulate transcriptional landscape during juvenile to adult transition in the parasitic helminth Schistosoma mansoni.

[This corrects the article DOI: 10.1371/journal.pntd.0005559.].