Improved survival for dose-intensive chemotherapy in primary mediastinal B-cell lymphoma: a systematic review and meta-analysis of 4,068 patients.

Primary mediastinal B-cell lymphoma (PMBCL) is a distinct clinicopathologic entity. Currently, there is a paucity of randomized prospective data to inform on optimal front-line chemoimmunotherapy (CIT) and use of consolidative mediastinal radiation (RT). To assess if distinct CIT approaches are associated with disparate survival outcomes, we performed a systematic review and meta-analysis comparing dose-intensive (DI-CIT) versus standard CIT for the front-line treatment of PMBCL. Standard approach (S-CIT) was defined as R-CHOP-21/CHOP-21, with or without RT. DI-CIT were defined as regimens with increased frequency, dose, and/or number of systemic agents. We reviewed data on 4,068 patients (2,517 DI-CIT; 1,551 S-CIT) with a new diagnosis of PMBCL. Overall survival for DI-CIT patients was 88% (95% CI: 85-90) compared to 80% for the S-CIT cohort (95% CI: 74-85). Meta-regression revealed an 8% overall survival (OS) benefit for the DI-CIT group (P<0.01). Survival benefit was maintained when analyzing rituximab only regimens; OS was 91% (95% CI: 89-93) for the rituximab-DI-CIT arm compared to 86% (95% CI: 82-89) for the R-CHOP-21 arm (P=0.03). Importantly, 55% (95% CI: 43-65) of the S-CIT group received RT compared to 22% (95% CI: 15-31) of DI-CIT patients (meta-regression P<0.01). To our knowledge, this is the largest meta-analysis reporting efficacy outcomes for the front-line treatment of PMBCL. DI-CIT demonstrates a survival benefit, with significantly less radiation exposure, curtailing long-term toxicities associated with radiotherapy. As we await results of randomized prospective trials, our study supports the use of dose-intensive chemoimmunotherapy for the treatment of PMBCL.

Takotsubo syndrome is a coronary microvascular disease: experimental evidence.

BACKGROUND AND AIMS: Takotsubo syndrome (TTS) is a conundrum without consensus about the cause. In a murine model of coronary microvascular dysfunction (CMD), abnormalities in myocardial perfusion played a key role in the development of TTS. METHODS AND RESULTS: Vascular Kv1.5 channels connect coronary blood flow to myocardial metabolism and their deletion mimics the phenotype of CMD. To determine if TTS is related to CMD, wild-type (WT), Kv1.5-/-, and TgKv1.5-/- (Kv1.5-/- with smooth muscle-specific expression Kv1.5 channels) mice were studied following transaortic constriction (TAC). Measurements of left ventricular (LV) fractional shortening (FS) in base and apex, and myocardial blood flow (MBF) were completed with standard and contrast echocardiography. Ribonucleic Acid deep sequencing was performed on LV apex and base from WT and Kv1.5-/- (control and TAC). Changes in gene expression were confirmed by real-time-polymerase chain reaction. MBF was increased with chromonar or by smooth muscle expression of Kv1.5 channels in the TgKv1.5-/-. TAC-induced systolic apical ballooning in Kv1.5-/-, shown as negative FS (P < 0.05 vs. base), which was not observed in WT, Kv1.5-/- with chromonar, or TgKv1.5-/-. Following TAC in Kv1.5-/-, MBF was lower in LV apex than in base. Increasing MBF with either chromonar or in TgKv1.5-/- normalized perfusion and function between LV apex and base (P = NS). Some genetic changes during TTS were reversed by chromonar, suggesting these were independent of TAC and more related to TTS. CONCLUSION: Abnormalities in flow regulation between the LV apex and base cause TTS. When perfusion is normalized between the two regions, normal ventricular function is restored.

Comparative analysis of trilobal capillary-channeled polymer fiber columns with superficially porous and monolithic phases toward reversed-phase protein separations.

A trilobal capillary-channeled polymer fiber stationary phase is evaluated for its performance for intact protein separations under reversed-phase high-performance liquid chromatography conditions. The separation quality, operational characteristics, and protein dynamic loading capacity on the fiber phases are compared to commercially-available superficially porous and monolithic columns. The trilobal or "y-shaped" polypropylene fiber phase was employed to separate a synthetic mixture of five proteins (having diverse chemistries and molecular weights). The separation quality was evaluated based on the resolution, peak heights/recoveries, peak widths, and peak areas. The present work illustrates the unique ability to operate at higher linear velocities (47.5 mm/s) while maintaining lower back pressures (∼4 MPa), faster separation times (<8 min), and faster gradient rates using the fiber columns while yielding comparable chromatographic performance to the commercial columns. The separations employing the commercial stationary phases operate at lower linear velocities (∼3.0 mm/s), higher back pressures (∼9 MPa), require longer separation times (10 min), and require slightly higher compositions of organic mobile phase to effect protein elution. Likewise, based on breakthrough loading analysis of lysozyme and bovine serum albumin, the trilobal, polypropylene C-CP fiber column stationary phases demonstrate 3-9X greater binding capacities on a bed volume basis versus the commercial columns.

Public attitudes towards novel reproductive technologies: a citizens' jury on mitochondrial donation.

STUDY QUESTION: Does an informed group of citizens endorse the clinical use of mitochondrial donation in a country where this is not currently permitted? SUMMARY ANSWER: After hearing balanced expert evidence and having opportunity for deliberation, a majority (11/14) of participants in a citizens' jury believed that children should be able to be born using mitochondrial donation. WHAT IS KNOWN ALREADY: Research suggests that patients, oocyte donors and health professionals support mitochondrial donation to prevent transmission of mitochondrial disease. Less is known about public acceptability of this novel reproductive technology, especially from evidence using deliberative methods. STUDY DESIGN, SIZE, DURATION: This study comprised a citizens' jury, an established method for determining the views of a well-informed group of community members. The jury had 14 participants, and ran over one and a half days in 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Jurors were members of the public with no experience of mitochondrial disease. They heard and engaged with relevant evidence and were asked to answer the question: 'Should Australia allow children to be born following mitochondrial donation?' MAIN RESULTS AND THE ROLE OF CHANCE: Eleven jurors decided that Australia should allow children to be born following mitochondrial donation; 7 of whom added conditions such as the need to limit who can access the intervention. Three jurors decided that children should not (or not yet) be born using this intervention. All jurors were particularly interested in the reliability of evidence, licensing/regulatory mechanisms and the rights of children to access information about their oocyte donors. LIMITATIONS, REASONS FOR CAUTION: Jurors' views were well informed and reflected critical deliberation and discussion, but are not intended to be representative of the whole population. WIDER IMPLICATIONS OF THE FINDINGS: When presented with high quality evidence, combined with opportunities to undertake structured deliberation of novel reproductive technologies, members of the public are able to engage in detailed discussions. This is the first study to use an established deliberative method to gauge public views towards mitochondrial donation. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by a University of Sydney Industry and Community Collaboration Seed Award (2017), which was awarded contingent on additional funding from the Mito Foundation. Additional funding was provided by the Mito Foundation. The Foundation was not involved in jury facilitation or deliberation, nor analysis of research data. TRIAL REGISTRATION NUMBER: Not applicable.

Breaking down frailty: Assessing vulnerability in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a disease primarily affecting older adults. However, not all patients at older ages are suitable for curative treatment with intensive chemotherapy due to "frailty" demonstrated by their functional status, physiologic reserve, and vulnerability to disease and treatment morbidity. Lack of consensus exists on how to select older, less fit patients most appropriate for standard intensive chemotherapy (IC), hypomethylating agents (HMA) with venetoclax, or less intensive regimens. A total of 37 studies of frailty assessments and composite indices in AML show heterogeneous results regarding the ability of frailty and Comprehensive Geriatric Assessment (CGA) measures to predict treatment outcomes. CGA, Geriatric 8 (G8) risk score, and hematopoietic cell transplant comorbidity index (HCT-CI) show association with prognosis, and should be validated in larger therapeutic trials. Studies of biomarkers, like albumin and C-reactive protein, and patient-reported outcomes demonstrate the potential to enhance information gained from rigorous geriatric assessment.

DREAM On, DREAM Off: A Review of the Estrogen Paradox in Luminal A Breast Cancers.

It is generally assumed that all estrogen-receptor-positive (ER+) breast cancers proliferate in response to estrogen and, therefore, examples of the estrogen-induced regression of ER+ cancers are paradoxical. This review re-examines the estrogen regression paradox for the Luminal A subtype of ER+ breast cancers. The proliferative response to estrogen is shown to depend on the level of ER. Mechanistically, a window of opportunity study of pre-operative estradiol suggested that with higher levels of ER, estradiol could activate the DREAM-MMB (Dimerization partner, Retinoblastoma-like proteins, E2F4, and MuvB-MYB-MuvB) pathway to decrease proliferation. The response of breast epithelium and the incidence of breast cancers during hormonal variations that occur during the menstrual cycle and at the menopausal transition, respectively, suggest that a single hormone, either estrogen, progesterone or androgen, could activate the DREAM pathway, leading to reversible cell cycle arrest. Conversely, the presence of two hormones could switch the DREAM-MMB complex to a pro-proliferative pathway. Using publicly available data, we examine the gene expression changes after aromatase inhibitors and ICI 182,780 to provide support for the hypothesis. This review suggests that it might be possible to integrate all current hormonal therapies for Luminal A tumors within a single theoretical schema.

Donor-Derived Malignancy and Transplantation Morbidity: Risks of Patient and Donor Genetics in Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a key treatment option for hematologic malignancies (HMs), although it carries significant risks. Up to 30% of patients relapse after allo-HSCT, of which up to 2% to 5% are donor-derived malignancies (DDMs). DDMs can arise from a germline genetic predisposition allele or clonal hematopoiesis (CH) in the donor. Increasingly, genetic testing reveals that patient and donor genetic factors contribute to the development of DDM and other allo-HSCT complications. Deleterious germline variants in CEBPA, DDX41, GATA2, and RUNX1 predispose to inferior allo-HSCT outcomes. DDM has been linked to donor-acquired somatic CH variants in DNMT3A, ASXL1, JAK2, and IDH2, often with additional new variants. We do not yet have evidence to standardize donor genetic sequencing prior to allo-HSCT. The presence of hereditary HM disorders should be considered in patients with myeloid malignancies and their related donors, and screening of unrelated donors should include family and personal history of cytopenia and HMs. Excellent multidisciplinary care is critical to ensure efficient timelines for screening and necessary discussions among medical oncologists, genetic counselors, recipients, and potential donors. After allo-HSCT, HM relapse monitoring with genetic testing effectively results in genetic sequencing of the donor, as the transplanted hematopoietic system is donor-derived, which presents ethical challenges for disclosure to patients and donors. We encourage consideration of the recent National Marrow Donor Program policy that allows donors to opt-in for notification about detection of their genetic variants after allo-HSCT, with appropriate genetic counseling when feasible. We look forward to prospective investigation of the impact of germline and acquired somatic genetic variants on hematopoietic stem cell mobilization/engraftment, graft-versus-host disease, and DDM to facilitate improved outcomes through knowledge of genetic risk.

Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development.

Periconceptional folic acid supplementation reduces the occurrence of several human congenital malformations, including craniofacial, heart and neural tube defects. Although the underlying mechanism is unknown, there may be a maternal-to-fetal folate-transport defect or an inherent fetal biochemical disorder that is neutralized by supplementation. Previous experiments have identified a folate-binding protein (Folbp1) that functions as a membrane receptor to mediate the high-affinity internalization and delivery of folate to the cytoplasm of the cell. In vitro, this receptor facilitates the accumulation of cellular folate a thousand-fold relative to the media, suggesting that it may be essential in cytoplasmic folate delivery in vivo. The importance of an adequate intracellular folate pool for normal embryogenesis has long been recognized in humans and experimental animals. To determine whether Folbp1 is involved in maternal-to-fetal folate transport, we inactivated Folbp1 in mice. We also produced mice lacking Folbp2, another member of the folate receptor family that is GPI anchored but binds folate poorly. Folbp2-/- embryos developed normally, but Folbp1-/- embryos had severe morphogenetic abnormalities and died in utero by embryonic day (E) 10. Supplementing pregnant Folbp1+/- dams with folinic acid reversed this phenotype in nullizygous pups. Our results suggest that Folbp1 has a critical role in folate homeostasis during development, and that functional defects in the human homologue (FOLR1) of Folbp1 may contribute to similar defects in humans.

DREAM, a possible answer to the estrogen paradox of the Women's Health Initiative Trial.

Estrogen is thought to cause proliferation of all estrogen receptor positive (ER+) breast cancers. Paradoxically, in the Women's Health Initiative Trial, estrogen-only hormone replacement therapy reduced the incidence and mortality of low grade, ER+, HER2- breast cancer. We gave estradiol to 19 post-menopausal women with newly diagnosed low-grade, ER+, HER2- breast cancer in a prospective window of opportunity clinical trial and examined the changes in proliferation and gene expression before and after estradiol treatment. Ki67 decreased in 13/19 (68%) patients and 8/13 (62%) showed a decrease in Risk of Recurrence Score. We chose three prototypical estrogen responders (greatest decrease in ROR) and non-responders (no/minimal change in ROR) and applied a differential gene expression analysis to develop pre-treatment (PRESTO-30core) and post-treatment (PRESTO-45surg) gene expression profiles. The PRESTO-30core predicted adjuvant benefit in a published series of tamoxifen, the partial estrogen agonist. Of the 45 genes in the PRESTO-45surg, thirty contain the Cell cycle genes Homology Region (CHR) motif that binds the class B multi-vulva complex (MuvB) a member of the DREAM (Dimerization partner, retinoblastoma-like proteins, E2F, MuvB) complex responsible for reversible cell cycle arrest or quiescence. There was also near uniform suppression (89%) of the remaining DREAM genes consistent with estrogen induced activation of the DREAM complex to mediate cell cycle block after a short course of estrogens. To our knowledge, this is the first report to show estrogen modulation of DREAM genes and suggest involvement of DREAM pathway associated quiescence in endocrine responsive post-menopausal ER+ breast cancers.

The evolution of dog diet and foraging: Insights from archaeological canids in Siberia.

Research on the evolution of dog foraging and diet has largely focused on scavenging during their initial domestication and genetic adaptations to starch-rich food environments following the advent of agriculture. The Siberian archaeological record evidences other critical shifts in dog foraging and diet that likely characterize Holocene dogs globally. By the Middle Holocene, body size reconstruction for Siberia dogs indicates that most were far smaller than Pleistocene wolves. This contributed to dogs' tendencies to scavenge, feed on small prey, and reduce social foraging. Stable carbon and nitrogen isotope analysis of Siberian dogs reveals that their diets were more diverse than those of Pleistocene wolves. This included habitual consumption of marine and freshwater foods by the Middle Holocene and reliance on C4 foods by the Late Holocene. Feeding on such foods and anthropogenic waste increased dogs' exposure to microbes, affected their gut microbiomes, and shaped long-term dog population history.

Donation after cardiac death: community views about 'decent' intervals.

Donation after cardiac death (DCD) offers an alternative pathway to donation for some donors. Successful recovery of organs for transplantation following DCD requires that organ recovery surgery commence as soon as possible after death has occurred. This limits the amount of time that family and friends can spend with the donor prior to surgery. The aim of this study was to identify community views about the timing of organ recovery in DCD. Data were collected from two sources in South Australia: 32 members of the public participated in four focus groups, and 2693 adults participated in a representative population survey. Respondents were asked their views about a decent interval to wait after death prior to organ recovery surgery. Focus group participants identified a tension between preserving organ viability and allowing families time with the deceased. Of the survey respondents, 45.2% selected a timeframe compatible with potentially viable donations; 34.1% selected a timeframe incompatible with viable donations; and 20.8% gave an indeterminate answer. These findings provide information about public perceptions of DCD, can be used to inform educational campaigns about DCD and serve as a baseline for evaluating such campaigns, and identify a number of areas for further investigation.

Defining intra-operative hypotension--a pilot comparison of blood pressure during sleep and general anaesthesia.

The scientific justification for particular values of intra-operative hypotension is poorly substantiated. To provide a rationale for appropriate values we recorded blood pressure measurements at home for 24 h using an automated non-invasive ambulatory blood pressure measurement device. These blood pressures were compared with blood pressure measured before and during general anaesthesia in 18 subjects undergoing elective day surgery. We confirmed that a pre-operative reading taken upon admission to hospital is significantly elevated compared to a usual daytime blood pressure in the same patient. The median (IQR [range]) increases in systolic and mean arterial pressures were 10 (2-15 [-5 to 59]) mmHg, p = 0.003 and 10 (5-14 [-5 to 35]) mmHg, p = 0.002, respectively. When using this admission blood pressure measurement as a 'baseline', systolic and mean arterial pressures decreased during sleep by 41 (30-46 [6-83]) mmHg and 34 (26-36 [6-58]) mmHg, respectively (p = 0.001). This decreased even further intra-operatively: systolic blood pressure by 49 (36-64 [15-96]) mmHg and mean arterial pressure by 36 (26-46 [8-66]) mmHg (p = 0.001).

Discrimination as A Barrier to Romani Women's Health and Empowerment: A Qualitative Study.

This qualitative descriptive case study investigates perceptions of health and empowerment among Romani women and social workers in Marseille, France. I used constructivist grounded theory to develop theory emerging from interviews and participant observation data. Results suggest intersectional discrimination at individual and structural levels led to inequalities in accessing resources essential to their survival in France, including healthcare, housing, and employment. This study provides insight into the ways discrimination impacts health inequalities experienced by Romani migrant women. Ultimately, this research highlights essential knowledge and strategies for social workers and public health professionals to empower Romani women by connecting them with essential resources and by envisioning anti-racist interventions to alleviate their experience of individual and structural discrimination.

Programmed death-1 receptor and interleukin-10 in liver transplant recipients at high risk for late cytomegalovirus disease.

Despite significant advances in antiviral treatment, solid organ transplant (SOT) recipients remain at heightened risk for developing late cytomegalovirus (CMV) disease. Elevated inhibitory immune signaling suggests a state of immune impairment in SOT recipients, who do not control CMV infection and develop severe clinical symptoms after discontinuation of antiviral prophylaxis. We longitudinally monitored the negative immune modulator programmed death (PD)-1 receptor on both CD4 and CD8 T cells, co-expressing the CD137 surface marker of recent activation, in a liver transplant cohort. Liver recipients who progressed to CMV disease expressed elevated levels of PD-1 on CD137(+) CD4 and CD8 T cells, following stimulation with either full-length peptide libraries or CMV lysate. This novel approach, applicable to a multitude of human leukocyte antigen types, enhances the usefulness of the PD-1 measurements as a clinical strategy to predict late CMV disease. In parallel, we detected an increased level of the immunosuppressive cytokine interleukin (IL)-10, in plasma of liver recipients diagnosed with CMV disease. CMV-specific T cells were still functional when both PD-1 and IL-10 were upregulated; however they showed a marked proliferation deficit, which may limit their ability to contain viremia and lead to CMV disease. Our preliminary observations support further investigation of dual monitoring of PD-1 and IL-10, as potential immune markers of CMV disease.

Electron Transfer in Microemulsion-Based Electrolytes.

The use of flowing electrochemical reactors, for example, in redox flow batteries and in various electrosynthesis processes, is increasing. This technology has the potential to be of central significance in the increased deployment of renewable electricity for carbon-neutral processes. A key element of optimizing efficiency of electrochemical reactors is the combination of high solution conductivity and reagent solubility. Here, we show a substantial rate of charge transfer for an electrochemical reaction occurring in a microemulsion containing electroactive material is loaded inside the nonpolar (toluene) subphase of the microemulsion. The measured rate constant translates to an exchange current density comparable to that in redox flow batteries. The rate could be controlled by the surfactant, which maintains partitioning of reactants and products by forming an interfacial region with ions in the aqueous phase in close proximity. The hypothesized mechanism is evocative of membrane-bound enzymatic reactions. Achieving sufficient rates of electrochemical reaction is the product of an effort designed to establish a reaction condition that meets the requirements of electrochemical reactors using microemulsions to realize a separation of conducting and reactive elements of the solution, opening a door to the broad use of microemulsions to effect controlled electrochemical reactions as steps in more complex processes.

Complementary DNA for the folate binding protein correctly predicts anchoring to the membrane by glycosyl-phosphatidylinositol.

Membrane bound and soluble forms of a high-affinity folate binding protein have been found in kidney, placenta, serum, milk, and in several cell lines. The two forms have similar binding characteristics for folates, are immunologically cross-reactive and based upon limited amino acid sequence data, are nearly identical. Based upon pulse-chase experiments, a precursor-product relationship has been suggested. The membrane form has been shown to mediate the transport of folate in cells grown in physiological concentrations of folate. A function for the soluble form has not yet been identified. We constructed a cDNA library from a human carcinoma cell line, Caco-2, which expresses the membrane form abundantly. The library was screened and a near full-length cDNA for the folate binder was isolated. Transfection of COS cells with the cDNA inserted in an expression vector resulted in marked overexpression of a membrane-associated folate binder as assessed by direct binding of radiolabeled folate and by indirect immunofluorescence. The deduced amino acid sequence is not consistent with a typical membrane spanning domain but rather with a signal for anchoring via a glycosyl-phosphatidylinositol linkage. Release of the binder with a phosphatidylinositol-specific phospholipase C strongly supports this hypothesis.

Biliary tract infection and bacteraemia: presentation, structural abnormalities, causative organisms and clinical outcomes.

BACKGROUND: Biliary tract infection is a common cause of bacteraemia and is associated with high morbidity and mortality. Few papers describe blood culture isolates, underlying structural abnormalities and clinical outcomes in patients with bacteraemia. AIMS: To determine the proportion of bacteraemias caused by biliary tract infection and to describe patient demographics, underlying structural abnormalities and clinical outcomes in patients with bacteraemia. DESIGN: Prospective cohort study. METHODS: Biliary tract infection that caused bacteraemia was defined as a compatible clinical syndrome and a blood culture isolate consistent with ascending cholangitis. Patients aged 16 years and over were included in the study. From June 2003 to May 2005, demographic and clinical data were collected prospectively on all adult patients with bacteraemia. Radiological and endoscopic retrograde cholangiopancreatography findings were collected retrospectively. RESULTS: In 49 patients, the biliary tract was the site of infection for 39/592 (6.6%) community-acquired and 19/466 (4.1%) hospital-acquired episodes of bacteraemia. Three patients had mixed bacteraemias, and four had recurrent bacteraemia. The proportion of patients presenting with a structural abnormality was 34/49 (69%), and, of these structural abnormalities, 18/34 (53%) were pre-existing or newly diagnosed malignancies. Gram-negative organisms caused 55/58 (95%) episodes of bacteraemia. The most common Gram-negative organisms were Escherichia coli (34/55; 62%) and Klebsiella pneumoniae (14/55; 26%). Of the E coli isolates, 6/34 (18%) were extended spectrum beta-lactamase producers or multiply drug resistant. Thirty-day mortality was 7/49 (14%). There was no difference in time taken to administer an effective antibiotic to survivors and non-survivors (0.86 vs 1.05 days, respectively, p = 0.92). Of the seven who died, four died from septic shock within 48 h of admission caused by "susceptible" Gram-negative organisms. Two others died from disseminated malignancy. CONCLUSIONS: The proportion of bacteraemias caused by biliary tract infection was 5.5%. The most common infecting organisms were E coli and K pneumoniae. There was a strong association with choledocholithiasis and malignancies, both pre-existing and newly diagnosed. Death was uncommon but when it occurred was often caused by septic shock within 48 h of presentation.

A meta-analysis of sperm donation offspring health outcomes.

Although the use of donor sperm as a treatment modality for male infertility has become common place, the health outcomes for those conceived has been poorly studied. A structured search of the literature using PubMed, EMBASE and Cochrane Reviews was performed to investigate the health outcomes of offspring conceived from donor sperm. Eight studies were eligible and included in the review, and of these, three were included in a meta-analysis. Meta-analysis of clinical outcomes showed that donor sperm neonates are not at increased risk of being born of low birth weight (<2500 g), preterm (<37 weeks) or with increased incidences of birth defects, than spontaneously conceived neonates.