Loss of Endometrial Plasticity in Recurrent Pregnancy Loss

© 2015 AlphaMed Press.Menstruation drives cyclic activation of endometrial progenitor cells, tissue regeneration, and maturation of stromal cells, which differentiate into specialized decidual cells prior to and during pregnancy. Aberrant responsiveness of human endometrial stromal cells (HESCs) to deciduogenic cues is strongly associated with recurrent pregnancy loss (RPL), suggesting a defect in cellular maturation. MeDIP-seq analysis of HESCs did not reveal gross perturbations in CpG methylation in RPL cultures, although quantitative differences were observed in or near genes that are frequently deregulated in vivo. However, RPL was associated with a marked reduction in methylation of defined CA-rich motifs located throughout the genome but enriched near telomeres. Non-CpG methylation is a hallmark of cellular multipotency. Congruently, we demonstrate that RPL is associated with a deficiency in endometrial clonogenic cell populations. Loss of epigenetic stemness features also correlated with intragenic CpG hypomethylation and reduced expression of HMGB2, coding high mobility group protein 2. We show that knockdown of this sequence-independent chromatin protein in HESCs promotes senescence and impairs decidualization, exemplified by blunted time-dependent secretome changes. Our findings indicate that stem cell deficiency and accelerated stromal senescence limit the differentiation capacity of the endometrium and predispose for pregnancy failure. Stem Cells 2016;34:346-356 Recurrent pregnancy loss is caused by endometrial stem cell deficiency, triggering heightened tissue senescence and impaired decidualization

Assessing Global Surface Water Inundation Dynamics Using Combined Satellite Information from SMAP, AMSR2 and Landsat

A method to assess global land surface water (fw) inundation dynamics was developed by exploiting the enhanced fw sensitivity of L-band (1.4 GHz) passive microwave observations from the Soil Moisture Active Passive (SMAP) mission. The L-band fw (fw(sub LBand)) retrievals were derived using SMAP H-polarization brightness temperature (Tb) observations and predefined L-band reference microwave emissivities for water and land endmembers. Potential soil moisture and vegetation contributions to the microwave signal were represented from overlapping higher frequency (Tb) observations from AMSR2. The resulting (fw(sub LBand)) global record has high temporal sampling (1-3 days) and 36-km spatial resolution. The (fw(sub LBand)) annual averages corresponded favourably (R=0.84, p<0.001) with a 250-m resolution static global water map (MOD44W) aggregated at the same spatial scale, while capturing significant inundation variations worldwide. The monthly (fw(sub LBand)) averages also showed seasonal inundation changes consistent with river discharge records within six major US river basins. An uncertainty analysis indicated generally reliable (fw(sub LBand)) performance for major land cover areas and under low to moderate vegetation cover, but with lower accuracy for detecting water bodies covered by dense vegetation. Finer resolution (30-m) (fw(sub LBand)) results were obtained for three sub-regions in North America using an empirical downscaling approach and ancillary global Water Occurrence Dataset (WOD) derived from the historical Landsat record. The resulting 30-m (fw(sub LBand)) retrievals showed favourable spatial accuracy for water (70.71%) and land (98.99%) classifications and seasonal wet and dry periods when compared to independent water maps derived from Landsat-8 imagery. The new (fw(sub LBand)) algorithms and continuing SMAP and AMSR2 operations provide for near real-time, multi-scale monitoring of global surface water inundation dynamics and potential flood risk

The Cosmology Large Angular Scale Surveyor

The Cosmology Large Angular Scale Surveyor (CLASS) is a four telescope array designed to characterize relic primordial gravitational waves from inflation and the optical depth to reionization through a measurement of the polarized cosmic microwave background (CMB) on the largest angular scales. The frequencies of the four CLASS telescopes, one at 38 GHz, two at 93 GHz, and one dichroic system at 145/217 GHz, are chosen to avoid spectral regions of high atmospheric emission and span the minimum of the polarized Galactic foregrounds: synchrotron emission at lower frequencies and dust emission at higher frequencies. Low-noise transition edge sensor detectors and a rapid front-end polarization modulator provide a unique combination of high sensitivity, stability, and control of systematics. The CLASS site, at 5200 m in the Chilean Atacama desert, allows for daily mapping of up to 70\% of the sky and enables the characterization of CMB polarization at the largest angular scales. Using this combination of a broad frequency range, large sky coverage, control over systematics, and high sensitivity, CLASS will observe the reionization and recombination peaks of the CMB E- and B-mode power spectra. CLASS will make a cosmic variance limited measurement of the optical depth to reionization and will measure or place upper limits on the tensor-to-scalar ratio, $r$, down to a level of 0.01 (95\% C.L.)

The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells

Implantation requires coordinated interactions between the conceptus and surrounding decidual cells, but the involvement of clock genes in this process is incompletely understood. Circadian oscillations are predicated on transcriptional-translational feedback loops, which balance the activities of the transcriptional activators CLOCK (circadian locomotor output cycles kaput) and brain muscle arnt-like 1 and repressors encoded by PER (Period) and Cryptochrome genes. We show that loss of PER2 expression silences circadian oscillations in decidualizing human endometrial stromal cells (HESCs). Down-regulation occurred between 12 and 24 hours following differentiation and coincided with reduced CLOCK binding to a noncanonical E-box enhancer in the PER2 promoter. RNA sequencing revealed that premature inhibition of PER2 by small interfering RNA knockdown leads to a grossly disorganized decidual response. Gene ontology analysis highlighted a preponderance of cell cycle regulators among the 1121 genes perturbed upon PER2 knockdown. Congruently, PER2 inhibition abrogated mitotic expansion of differentiating HESCs by inducing cell cycle block at G2/M. Analysis of 70 midluteal endometrial biopsies revealed an inverse correlation between PER2 transcript levels and the number of miscarriages in women suffering reproductive failure (Spearman rank test, ρ = -0.3260; P = 0.0046). Thus, PER2 synchronizes endometrial proliferation with initiation of aperiodic decidual gene expression; uncoupling of these events may cause recurrent pregnancy loss.-Muter, J., Lucas, E. S., Chan, Y.-W., Brighton, P. J., Moore, J. D., Lacey, L., Quenby, S., Lam, E. W.-F., Brosens, J. J. The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells

Lentivirus-induced 'Smart' dendritic cells:Pharmacodynamics and GMP-compliant production for immunotherapy against TRP2 positive melanoma

Monocyte-derived conventional dendritic cells (ConvDCs) loaded with melanoma antigens showed modest responses in clinical trials. Efficacy studies were hampered by difficulties in ConvDC manufacturing and low potency. Overcoming these issues, we demonstrated higher potency of lentiviral vector (LV)-programmed DCs. Monocytes were directly induced to self-differentiate into DCs (SmartDCTRP2) upon transduction with a tricistronic LV encoding for cytokines (granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4)) and a melanoma antigen (tyrosinase-related protein 2 (TRP2)). Here, SmartDC-TRP2 generated with monocytes from five advanced melanoma patients were tested in autologous DC:T cell stimulation assays, validating the activation of functional TRP2-specific cytotoxic T lymphocytes (CTLs) for all patients. We described methods compliant to good manufacturing practices (GMP) to produce LV and SmartDC-TRP2. Feasibility of monocyte transduction in a bag system and cryopreservation following a 24-h standard operating procedure were achieved. After thawing, 50% of the initial monocyte input was recovered and SmartDC-TRP2 selfdifferentiated in vitro, showing uniform expression of DC markers, detectable LV copies and a polyclonal LV integration pattern not biased to oncogenic loci. GMP-grade SmartDC-TRP2 expanded TRP2-specific autologous CTLs in vitro. These results demonstrated asimpler GMP-compliant method of manufacturing an effective individualized DC vaccine. Such DC vaccine, when in combination with checkpoint inhibition therapies, might provide higher specificity against melanoma

“Breaking up is hard to do”: the formation and resolution of sister chromatid intertwines

The absolute necessity to resolve every intertwine between the two strands of the DNA double helix provides a massive challenge to the cellular processes that duplicate and segregate chromosomes. Although the overwhelming majority of intertwines between the parental DNA strands are resolved during DNA replication, there are numerous chromosomal contexts where some intertwining is maintained into mitosis. These mitotic sister chromatid intertwines (SCIs) can be found as; short regions of unreplicated DNA, fully replicated and intertwined sister chromatids—commonly referred to as DNA catenation—and as sister chromatid linkages generated by homologous recombination-associated processes. Several overlapping mechanisms, including intra-chromosomal compaction, topoisomerase action and Holliday junction resolvases, ensure that all SCIs are removed before they can prevent normal chromosome segregation. Here, I discuss why some DNA intertwines persist into mitosis and review our current knowledge of the SCI resolution mechanisms that are employed in both prokaryotes and eukaryotes, including how deregulating SCI formation during DNA replication or disrupting the resolution processes may contribute to aneuploidy in cancer

Deregulation of the endometrial stromal cell secretome precedes embryo implantation failure

STUDY QUESTION Is implantation failure following ART associated with a perturbed decidual response in endometrial stromal cells (EnSCs)? SUMMARY ANSWER Dynamic changes in the secretome of decidualizing EnSCs underpin the transition of a hostile to a supportive endometrial microenvironment for embryo implantation; perturbation in this transitional pathway prior to ART is associated with implantation failure. WHAT IS KNOWN ALREADY Implantation is the rate-limiting step in ART, although the contribution of an aberrant endometrial microenvironment in IVF failure remains ill defined. STUDY DESIGN, SIZE, DURATION In vitro characterization of the temporal changes in the decidual response of primary EnSCs isolated prior to a successful or failed ART cycle. An analysis of embryo responses to secreted cues from undifferentiated and decidualizing EnSCs was performed. The primary clinical outcome of the study was a positive urinary pregnancy test 14 days after embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS Primary EnSCs were isolated from endometrial biopsies obtained prior to IVF treatment and cryopreserved. EnSCs from 10 pregnant and 10 non-pregnant patients were then thawed, expanded in culture, subjected to clonogenic assays, and decidualized for either 2 or 8 days. Transcript levels of decidual marker gene [prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP1) and 11β-hydroxysteroid dehydrogenase (HSD11B1)] were analysed using real-time quantitative PCR and temporal secretome changes of 45 cytokines, chemokines and growth factors were measured by multiplex suspension bead immunoassay. The impact of the EnSC secretome on human blastocyst development was scored morphologically; and embryo secretions in response to EnSC cues analyzed by multiplex suspension bead immunoassay. MAIN RESULTS AND THE ROLE OF CHANCE Clonogenicity and induction of decidual marker genes were comparable between EnSC cultures from pregnant and non-pregnant group groups (P > 0.05). Analysis of 23 secreted factors revealed that successful implantation was associated with co-ordinated secretome changes in decidualizing EnSCs, which were most pronounced on Day 2 of differentiation: 17 differentially secreted proteins on Day 2 of decidualization relative to undifferentiated (Day 0) EnSCs (P 0.05)

Cancer survivors' experience with telehealth: A systematic review and thematic synthesis

Background: Net survival rates of cancer are increasing worldwide, placing a strain on health service provision. There is a drive to transfer the care of cancer survivors—individuals living with and beyond cancer—to the community and encourage them to play an active role in their own care. Telehealth, the use of technology in remote exchange of data and communication between patients and health care professionals (HCPs), is an important contributor to this evolving model of care. Telehealth interventions are “complex,” and understanding patient experiences of them is important in evaluating their impact. However, a wider view of patient experience is lacking as qualitative studies detailing cancer survivor engagement with telehealth are yet to be synthesized. Objective: To systematically identify, appraise, and synthesize qualitative research evidence on the experiences of adult cancer survivors participating in telehealth interventions, to characterize the patient experience of telehealth interventions for this group. Methods: Medline (PubMed), PsychINFO, Cumulative Index for Nursing and Allied Health Professionals (CINAHL), Embase, and Cochrane Central Register of Controlled Trials were searched on August 14, 2015, and March 8, 2016, for English-language papers published between 2006 and 2016. Inclusion criteria were as follows: adult cancer survivors aged 18 years and over, cancer diagnosis, experience of participating in a telehealth intervention (defined as remote communication or remote monitoring with an HCP delivered by telephone, Internet, or hand-held or mobile technology), and reporting qualitative data including verbatim quotes. An adapted Critical Appraisal Skill Programme (CASP) checklist for qualitative research was used to assess paper quality. The results section of each included article was coded line by line, and all papers underwent inductive analysis, involving comparison, reexamination, and grouping of codes to develop descriptive themes. Analytical themes were developed through an iterative process of reflection on, and interpretation of, the descriptive themes within and across studies. Results: Across the 22 included papers, 3 analytical themes emerged, each with 3 descriptive subthemes: (1) influence of telehealth on the disrupted lives of cancer survivors (convenience, independence, and burden); (2) personalized care across physical distance (time, space, and the human factor); and (3) remote reassurance—a safety net of health care professional connection (active connection, passive connection, and slipping through the net). Telehealth interventions represent a convenient approach, which can potentially minimize treatment burden and disruption to cancer survivors’ lives. Telehealth interventions can facilitate an experience of personalized care and reassurance for those living with and beyond cancer; however, it is important to consider individual factors when tailoring interventions to ensure engagement promotes benefit rather than burden. Conclusions: Telehealth interventions can provide cancer survivors with independence and reassurance. Future telehealth interventions need to be developed iteratively in collaboration with a broad range of cancer survivors to maximize engagement and benefit