Rural residence is related to shorter survival in epithelial ovarian cancer patients.

OBJECTIVE: Rural residence has been related to health disparities and greater mortality risk in cancer patients, including gynecologic cancer patients. Lower survival rates for rural cancer survivors have been attributed to limited access to specialized healthcare, including surgery. Here, we examined whether a rural/urban survival gap existed in ovarian cancer patients receiving surgery at tertiary-care facilities, and potential causes for this gap, including educational attainment. METHODS: Rural and urban patients with high grade invasive ovarian cancer (n = 342) seeking treatment at two midwestern tertiary-care university hospitals were recruited pre-surgery and followed until death or censoring date. Rural/urban residence was categorized using the USDA Rural-Urban Continuum Codes. Stratified Cox proportional hazards regression analyses, with clinical site as strata, adjusting for clinical and demographic covariates, were used to examine the effect of rurality on survival. RESULTS: Despite specialized surgical care, rural cancer survivors showed a higher likelihood of death compared to their urban counterparts, HR = 1.39 (95% CI: 1.04, 1.85) p = 0.026, adjusted for covariates. A rurality by education interaction was observed (p = 0.027), indicating significantly poorer survival in rural vs. urban patients among those with trade school/some college education, adjusted HR = 2.49 (95% CI: 1.44, 4.30), p = 0.001; there was no rurality survival disparity for the other 2 levels of education. CONCLUSIONS: Differences in ovarian cancer survival are impacted by rurality, which is moderated by educational attainment even in patients receiving initial care in tertiary settings. Clinicians should be aware of rurality and education as potential risk factors for adverse outcomes and develop approaches to address these possible risks.

Human definitive hematopoietic specification from pluripotent stem cells is regulated by mesodermal expression of CDX4.

The generation of hematopoietic stem cells from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. Achieving this goal is complicated by our incomplete understanding of the mechanism regulating definitive hematopoietic specification. We used our stage-specific hPSC differentiation method to obtain and identify, via CD235a expression, mesoderm harboring exclusively primitive or definitive hematopoietic potential to understand the genetic regulation of definitive hematopoietic specification. Whole-transcriptome gene expression analyses on WNT-dependent KDR+CD235a- definitive hematopoietic mesoderm and WNT-independent KDR+CD235a+ primitive hematopoietic mesoderm revealed strong CDX gene expression within definitive hematopoietic mesoderm. Temporal expression analyses revealed that CDX4 was expressed exclusively within definitive hematopoietic KDR+CD235a- mesoderm in a WNT- and fibroblast growth factor-dependent manner. We found that exogenous CDX4 expression exclusively during mesoderm specification resulted in a >90% repression in primitive hematopoietic potential, but conferred fivefold greater definitive hematopoietic potential, similar to that observed following WNT stimulation. In contrast, CDX4 knockout hPSCs had intact primitive hematopoietic potential, but exhibited a fivefold decrease in multilineage definitive hematopoietic potential. Taken together, these findings indicate that CDX4 is a critical transcription factor in the regulation of human definitive hematopoietic specification, and provides a mechanistic basis for WNT-mediated definitive hematopoietic specification from hPSCs.

Murine cytomegalovirus protein pM79 is a key regulator for viral late transcription.

Herpesvirus genes are temporally expressed during permissive infections, but how their expression is regulated at late times is poorly understood. Previous studies indicate that the human cytomegalovirus (CMV) gene, UL79, is required for late gene expression. However, the mechanism remains to be fully elucidated, and UL79 homologues in other CMVs have not been studied. Here, we characterized the role of the conserved murine CMV (MCMV) gene M79. We showed that M79 encoded a protein (pM79) which was expressed with early-late kinetics and localized to nuclear viral replication compartments. M79 transcription was significantly decreased in the absence of viral DNA synthesis but markedly stimulated by pM79. To investigate its role, we created the recombinant virus SMin79, in which pM79 expression was disrupted. While marker-rescued virus grew efficiently in fibroblasts, SMin79 failed to produce infectious progeny but was rescued by pM79 expression in trans. During SMin79 infection, representative viral immediate-early and early gene products as well as viral DNA accumulated sufficiently. Formation of viral replication compartments also appeared normal. Pulsed-field gel electrophoresis analysis indicated that the overall structure of replicating viral DNA was indistinguishable between wild-type and SMin79 infection. Viral tiled array and quantitative PCR analysis revealed that many late transcripts sensitive to a viral DNA synthesis inhibitor (phosphonoacetic acid) were markedly reduced by pM79 mutation. This study indicates that cytomegaloviruses use a conserved mechanism to promote transcription at late stages of infection and that pM79 is a critical regulator for at least a subset of viral DNA synthesis-dependent transcripts.

DERM Author Taken to the Cleaners by a Reviewer: So, Do You Think the Reviewer of Your Submission Was Unkind? Read This.

Highly critical reviews of medical books are rarely encountered in our age, but this was not always the case. I provide an example of a very negative review of an early medical book that may have blocked the author from further publication.Papers published in reputable journals are subjected to review by experts, whose task is to find weakness in research and/or flaws in its arguments. Published reviews of textbooks that appear these days are generally laudatory, calling attention to the strengths of the book with little mention of any shortcomings. Non-meritorious works are usually winnowed out by the editing process and never make it to publication.

RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer.

PURPOSE: To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples. EXPERIMENTAL DESIGN: RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated. RESULTS: RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P < 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P < 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78-1.0; P < 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33-0.85; P < 0.001) and overall survival (HR, 0.43; 95% CI, 0.25-0.75; P = 0.003) than RAD51-High status. CONCLUSIONS: RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.

Gynecologic oncology patient perspectives and knowledge on advance care planning: A quality improvement intervention.

Objectives: Assess and improve advance care planning (ACP) awareness and uptake among gynecologic oncology patients. Methods: Using a quality improvement Plan-Do-Check-Act framework, we completed a single institution needs assessment and intervention. The needs assessment was a 26-question survey assessing baseline ACP knowledge and preferences of gynecologic oncology patients. We used this survey to implement an outpatient intervention in which patients were offered ACP resources (pamphlet, discussion with their gynecologic oncologist, and/or social work referral). We conducted a post-intervention survey among patients who had and had not received ACP resource(s) to assess whether our intervention increased ACP knowledge, discussions, or uptake. Results: Among 106 patients surveyed in the needs assessment, 33 % had ACP documents, 26 % had discussed ACP with a physician, and 82 % thought discussing ACP was important. The majority preferred these conversations in the outpatient setting (52 %) with their gynecologic oncologist (80 %) instead of nurses or trainees. In the intervention, 526 patients were offered ACP resources. Compared to women who did not receive resources (n = 324), patients who received ACP resource(s) (n = 202) were more likely to have ACP discussions with their gynecologic oncologist (38 % vs 68 %, P = 0.001) and had greater proficiency regarding how to create ACP documents (median score 5/10 vs 8/10, P = 0.048), although they were no more likely to have ACP documented in their electronic medical record (27 % vs 9 %, p = 0.08). Conclusions: ACP uptake among gynecologic oncology patients is low, but ACP discussions with an oncologist during outpatient visits are important to patients and improve their knowledge regarding completing ACP documents.

Loss of KMT2C reprograms the epigenomic landscape in hPSCs resulting in NODAL overexpression and a failure of hemogenic endothelium specification.

Germline or somatic variation in the family of KMT2 lysine methyltransferases have been associated with a variety of congenital disorders and cancers. Notably, KMT2A-fusions are prevalent in 70% of infant leukaemias but fail to phenocopy short latency leukaemogenesis in mammalian models, suggesting additional factors are necessary for transformation. Given the lack of additional somatic mutation, the role of epigenetic regulation in cell specification, and our prior results of germline KMT2C variation in infant leukaemia patients, we hypothesized that germline dysfunction of KMT2C altered haematopoietic specification. In isogenic KMT2C KO hPSCs, we found genome-wide differences in histone modifications at active and poised enhancers, leading to gene expression profiles akin to mesendoderm rather than mesoderm highlighted by a significant increase in NODAL expression and WNT inhibition, ultimately resulting in a lack of in vitro hemogenic endothelium specification. These unbiased multi-omic results provide new evidence for germline mechanisms increasing risk of early leukaemogenesis.

Stability of murine cytomegalovirus genome after in vitro and in vivo passage.

While large DNA viruses are thought to have low mutation rates, only a small fraction of their genomes have been analyzed at the single-nucleotide level. Here, we defined the genetic stability of murine cytomegalovirus (MCMV) by whole-genome sequencing. Independently assembled sequences of three sister plaques showed only two single-base-pair substitutions after in vitro passage. In vivo-passaged MCMV likewise demonstrated low mutation rates, comparable to those after in vitro passage, indicating high genome stability of MCMV at the single-nucleotide level in the absence of obvious selection pressure.

Follicular variant of seborrheic dermatitis: is it identical to Malassezia folliculitis?

Follicular accentuation in some patients with seborrheic dermatitis of the back and chest has been recognized for more than a century. The recognition of Malassezia folliculitis in recent decades has led to some confusion regarding categorization of these cases. The author proposes that there is sufficient clinical variation between the typical case of Malassezia folliculitis and patients with follicular seborrheic dermatitis to justify continued separation of these entities until further study provides more clarification.

The association between state-level abortion restrictions and maternal mortality in the United States, 1995-2017.

OBJECTIVE: To explore the relationship between abortion restrictions and maternal mortality in the United States. STUDY DESIGN: This was a retrospective study examining maternal mortality in the United States from 1995 to 2017. We used the Global Health Data Exchange and the Centers for Disease Control and Prevention WONDER databases to extract maternal mortality data for all 50 states for each year from 1995 to 2017. We categorized states as restrictive, neutral, or protective of abortion access according to policy information published by the Guttmacher Institute. We assessed associations between abortion restrictions and maternal mortality ratios (maternal deaths per 100,000 live births). RESULTS: In 1995, the mean maternal mortality ratios were similar across all groups of states (Restrictive 12.6, 95% CI 11.4-13.6; Neutral 12.2, 95% CI 10.9-13.4; Protective 10.9, 95% CI 9.6-11.9). Maternal mortality ratios increased for each group of states over time and in 2017, the mean maternal mortality ratio was higher in restrictive states than in protective states (Restrictive 28.5, 95% CI 20.7-35.1; Neutral 22.9, 95% CI 16.1-28.6; Protective 15.7, 95% CI 10.7-19.9). Regressions accounting for policy, state and year showed a statistically significant increase in maternal mortality ratios in restrictive states relative to neutral states (1.06, 95% CI 1.01-1.11) and a non-significant decrease associated with protective states (0.89, 95% CI 0.78-1.01). CONCLUSIONS: States that restrict abortion have higher maternal mortality than states that either protect or are neutral towards abortion. Further investigation is needed to determine how abortion restrictions are associated with increased maternal mortality. IMPLICATIONS: The association between abortion restrictions and maternal mortality may reflect the overall legislative priorities of individual states as restrictive states are less likely to pass proactive legislation demonstrated to improve maternal outcomes.

RNA-Seq identifies genes whose proteins are upregulated during syncytia development in murine C2C12 myoblasts and human BeWo trophoblasts.

The fusion of villous cytotrophoblasts into the multinucleated syncytiotrophoblast is critical for the essential functions of the mammalian placenta. Using RNA-Seq gene expression, quantitative protein expression, and siRNA knockdown we identified genes and their cognate proteins which are similarly upregulated in two cellular models of mammalian syncytia development (human BeWo cytotrophoblast to syncytiotrophoblast and murine C2C12 myoblast to myotube). These include DYSF, PDE4DIP, SPIRE2, NDRG1, PLEC, GPR146, HSPB8, DHCR7, and HDAC5. These findings provide avenues for further understanding of the mechanisms underlying mammalian placental syncytiotrophoblast development.

Hereditary woolly hair and keratosis pilaris.

We describe a family with woolly hair and ulerythema ophryogenes spanning four generations. Both woolly hair and ulerythema ophryogenes have been associated with Noonan syndrome and cardiofaciocutaneous syndrome (CFC), two disorders with considerable phenotypic overlap. This family did not exhibit any of the other findings characteristic of either Noonan syndrome or CFC, similar to a previously described pedigree with hereditary woolly hair. Woolly hair elicits a broad differential diagnosis, including woolly hair nevus and several genodermatoses. Our report reviews the evaluation of woolly hair and discusses the conditions associated with this physical finding.

Mitochondrial genomics in Orthoptera using MOSAS.

We present complete mitochondrial genomes (mitogenomes) for three orthopterans (Xyleus modestus, Physemacris variolosa, and Ellipes minuta) and describe MOSAS (manipulation, organization, storage, and analysis of sequences), software we developed to facilitate annotation and analysis. We analyze the base composition, start and stop codons, non-coding regions, and gene order among these and 18 other orthopteran mitogenomes from GenBank and reconstruct a phylogeny of Orthoptera. We propose a tetranucleotide start codon for cox1, and hypothesize that the tRNA(Asp)-tRNA(Lys) rearrangement is a synapomorphy for Acridomorpha, but not Caelifera. We further describe MOSAS, user-friendly software we used for this analysis. MOSAS streamlines sequence data storage, organization, annotation, and alignment, and provides convenient search tools for dataset construction and a robust annotation engine particularly suited to annotating mitogenomes (available at http://mosas.byu.edu).

George Cheyne Shattuck's dissertation on the skin.

George Cheyne Shattuck's 1808 dissertation on structure and function of the skin is one of the earliest American writings on the topic of skin diseases. Although this essay contributed no important new observations, it does provide insight into the attitudes of American physicians in the post-Revolutionary War period toward skin diseases, their classification, and their management.