Germ cell tumors are a heterogeneous group of neoplasms derived from residual primordial tissue. These tumors are commonly found in the brain, testes, or ovaries, where they are termed germinomas, ...seminomas, or dysgerminomas, respectively. Like several other tumor types, germ cell tumors often harbor an immune cell infiltrate that can include substantial numbers of B cells. Yet little is known about whether the humoral immune response affects germ cell tumor biology. To gain a deeper understanding of the role B cells play in this tumor family, we characterized the immune cell infiltrate of all three germ cell tumor subtypes and defined the molecular characteristics of the B cell Ag receptor expressed by tumor-associated B cells. Immunohistochemistry revealed a prominent B cell infiltrate in the microenvironment of all tumors examined and clear evidence of extranodal lymphoid follicles with germinal center-like architecture in a subset of specimens. Molecular characterization of the Ig variable region from 320 sequences expressed by germ cell tumor-infiltrating B cells revealed clear evidence of Ag experience, in that the cardinal features of an Ag-driven B cell response were present: significant somatic mutation, isotype switching, and codon insertion/deletion. This characterization also revealed the presence of both B cell clonal expansion and variation, suggesting that local B cell maturation most likely occurs within the tumor microenvironment. In contrast, sequences from control tissues and peripheral blood displayed none of these characteristics. Collectively, these data strongly suggest that an adaptive and specific humoral immune response is occurring within the tumor microenvironment.
Chapter 1: The Astrobiology Primer 3.0 Schaible, Micah J; Szeinbaum, Nadia; Bozdag, G Ozan ...
Astrobiology,
03/2024, Letnik:
24, Številka:
S1
Journal Article
Recenzirano
The Astrobiology Primer 3.0 (ABP3.0) is a concise introduction to the field of astrobiology for students and others who are new to the field of astrobiology. It provides an entry into the broader ...materials in this supplementary issue of
and an overview of the investigations and driving hypotheses that make up this interdisciplinary field. The content of this chapter was adapted from the other 10 articles in this supplementary issue and thus represents the contribution of all the authors who worked on these introductory articles. The content of this chapter is not exhaustive and represents the topics that the authors found to be the most important and compelling in a dynamic and changing field.
Hospital benchmarking is essential to quality improvement, but its usefulness depends on the ability of statistical models to adequately control for inter-hospital differences in patient mix. We ...explored whether the addition of injury-specific clinical variables to the current American College of Surgeons-Trauma Quality Improvement Program (TQIP) algorithm would improve model fit.
We analyzed a prospective registry containing all adult patients who presented to a regional consortium of 14 trauma centers between 2010 and 2011 with severe traumatic brain injury (TBI). We used hierarchical logistic regression and stepwise forward selection to develop two novel risk-adjustment models. We then tested our novel models against the current TQIP model and ranked hospitals by their risk-adjusted mortality rates under each model to determine how model selection affects quality benchmarking.
Seven hundred thirty-four patients met inclusion criteria. Stepwise selection resulted in two distinct models: one that added three TBI-specific variables (pupil reactivity, cerebral edema, loss of basal cisterns) to the model specification currently used by TQIP and another that combined two TBI-specific variables (pupil reactivity, cerebral edema) with a three-variable subset of TQIP (age, Abbreviated Injury Scale score for the head region, Glasgow Coma Scale motor score). Both novel models outperformed TQIP. Although rankings remained largely unchanged across model configurations, several hospitals moved across quality terciles.
The inclusion of injury-specific variables improves risk adjustment for patients with severe TBI. Trauma Quality Improvement Program should consider replacing several of its general patient characteristics with injury-specific clinical predictors to increase efficiency, reduce the risk of overfitting, and improve the accuracy of hospital benchmarking.
Prognostic and epidemiological, level II.
Abstract
Experimental measurements of collision‐induced absorption (CIA) cross sections for CO
2
‐H
2
and CO
2
‐CH
4
complexes were performed using Fourier transform spectroscopy over a spectral ...range of 150–475 cm
−1
and a temperature range of 200–300 K. These experimentally derived CIA cross sections agree with the spectral range of the calculation by Wordsworth et al. (2017) however, the amplitude is half of what was predicted. Furthermore, the CIA cross sections reported here agree with those measured by Turbet et al. (2019, 2019). Additionally, radiative transfer calculations of the early Mars atmosphere were performed, and showed that CO
2
‐CH
4
CIA would require surface pressure greater than 3 bar for a 10% methane atmosphere to achieve 273 K at the surface. For CO
2
‐H
2
, liquid water is possible with 5% hydrogen and less than 2 bar of surface pressure.
Plain Language Summary
New temperature‐dependent infrared absorption properties of CO
2
‐H
2
and CO
2
‐CH
4
gas mixtures were experimentally tested against a theoretical prediction. Ultimately, we find that the strength of the absorption was half of what was predicted. Absorption between CO
2
‐H
2
and CO
2
‐CH
4
was proposed as a way to increase the greenhouse gas effect on ancient Mars, so that Mars would be warm enough to have liquid water on the surface. Ancient Mars climate was simulated using the new gas mixture absorption properties. Since the experimental absorption was weaker than predicted, we find that CO
2
‐CH
4
is insufficient in warming ancient Mars, but CO
2
‐H
2
remains a possibility.
Key Points
First experimental measurements of CO
2
‐H
2
and CO
2
‐CH
4
CIA cross sections at multiple temperatures
Radiative transfer calculations of the early Mars atmosphere were performed using the newly acquired CIA cross sections
Surface temperatures above 273 K can be reached if surface pressures exceed 3 bar for 10% CH
4
or 2 bar for a 5% H
2
atmosphere
Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of ...critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment.
An excavation conducted at Harewood Cemetery to identify the unmarked grave of Samuel Washington resulted in the discovery of burials presumably belonging to George Washington’s paternal grandnephews ...and their mother, Lucy Payne. To confirm their identities this study examined Y-chromosomal, mitochondrial, and autosomal DNA from the burials and a living Washington descendant. The burial’s Y-STR profile was compared to FamilyTreeDNA’s database, which resulted in a one-step difference from the living descendant and an exact match to another Washington. A more complete Y-STR and Y-SNP profile from the descendant was inferred to be the Washington Y profile. Kinship comparisons performed in relation to the descendant, who is a 4th and 5th degree relative of the putative individuals, resulted in >37,000 overlapping autosomal SNPs and strong statistical support with likelihood ratios exceeding one billion. This study highlights the benefits of a multi-marker approach for kinship prediction and DNA-assisted identification of historical remains.
Display omitted
•Washington burials from mid-1800s predicted to be a mother and two full siblings•Full siblings individualized using auSNPs of living “double Washington” descendant•Y-STR profile of the male burial consistent with living Washingtons in FTDNA•The Y-DNA profile of George Washington’s patriline belongs to haplogroup R-BY32422
Bioinformatics; Human genetics
A growing number of healthcare organizations have moved from traditional, institutional nursing home models to ones that emphasize culture change, or resident-centered care (RCC). In 2006, the ...Department of Veterans Affairs (VA) began implementing a number of changes to VA nursing homes, now called Community Living Centers (CLCs), to provide veterans with a more resident-centered and homelike environment. This study aimed to understand the barriers CLC staff face when delivering RCC. Ten CLCs were included on the basis of their performance levels on RCC and quality of care. Semistructured interviews that focused on facility efforts in RCC and quality were conducted with all levels of staff. Interviews were systematically content coded. We found similarities and differences in barriers reported at high- and low-performing sites. Staff across all performance levels cited 5 main categories of barriers to delivering RCC: staffing, resources, acuity of residents, RCC and quality of care conflicts, and regulations. Staff in high-performing sites reported fewer barriers to RCC, although 1 barrier cited was difficulty coordinating RCC across departments. Staff in low-performing sites reported additional categories of barriers related to administrator turnover/lack of guidance, CLC culture/staff morale, and difficulty working with residents and families. As RCC continues to spread, it is important to anticipate the barriers to implementing these practices. Particular focus on regulatory, leadership, organizational, workforce, and process factors may help organizations avoid or reduce barriers to RCC. Given their training and skill set, mental health providers may be uniquely situated to assist staff in overcoming these barriers.
Abstract only
88
Background: Management of HRPCa is a clinical challenge. Novel AR inhibitors could potentially impact outcome in HRPCa men following RP. We conducted a phase II study evaluating the ...efficacy/safety of Enza in men with HRPCa following RP. Methods: HRPCa pts (≥pT3a, GS≥8, iPSA ≥20 ng/mL, +ve lymph nodes (LN), or ≥35% chance of biochemical recurrence (BCR) at 5 yrs based on MSKCC’s nomogram) with undetectable PSA within 3 months from RP were eligible. Enza 160mg PO daily was given in 28-day cycles until disease progression, intolerability, consent withdrawal, or study completion at 24 months. Accrual goal was N=40 to provide 80% power to detect a 75% decrease in the risk of BCR from historical 55% rate. BCR was defined as PSA ≥0.2ng/mL on 2 consecutive lab results or any PSA rise that resulted in subsequent therapy. Results: 42 men enrolled. Median age 59 (range 43-70), based on biopsy 45% were GS7; 36% GS8, 19% GS9. 76% men had cT1, 24% cT2, median iPSA was 8.2 (range 2-77). On prostatectomy pathology: 50% had pT3b; 52% +ve margins; 50% SVI; 24% had +LN. 37 (88%) pts completed 24 planned cycles. Of the 5 pts who did not complete all cycles, 3 withdrew consent for toxicity (2 had G3 fatigue, 1 had G3 fatigue and arthralgias/myalgias), 1 had rising PSA requiring subsequent therapy, and 1 had financial concerns. With median follow-up of 31 months (range 2.5-44.5), 37 (88%) pts remain free of BCR. Of the 5 pts who developed BCR, 4 completed all 24 months on therapy. Median time to BCR was 31 months (range 13-40). Most common adverse events (AE) are listed (Table). Conclusions: Adjuvant Enza in men with HRPCa following RP is safe and relatively well-tolerated. Long-term safety, efficacy, and genomic correlations (including tumor RNA expression) are ongoing. Clinical trial information: NCT01927627. Table: see text
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