Human embryonic stem cells offer unprecedented potential for the study of human development and carry a significant promise for advancing the future of medical practice. HESCs are particularly useful for the study of tissues and organ systems that exhibit poor endogenous regenerative capabilities, like the adult CNS. The corticospinal tract is part of CNS, and is required for skilled voluntary movement of the hands, fingers, and toes. Fezf2 has been identified as an important marker and regulator of the corticospinal motor neuron (CSMN) fate in mouse models, and is evolutionarily preserved from drosophila to humans. Nevertheless, the role of Fezf2 in human cortical and CST development requires further elucidation. Here, using a Fezf2:EYFP knock-in hESC reporter line, we sought to clarify the role of Fezf2 in human cortical development, and attempted to generate human CSMNs. Through directed differentiation, we were able to guide our cells through the process of cortical development. We found that Fezf2 is broadly expressed in early human cortical stem/ progenitor cells, and verified that these Fezf2 positive cells are mitotic, demonstrating that human Fezf2 expression is not limited to deep-layer post mitotic neurons. Further, we were able to verify that as differentiation progresses, so does the molecular identity of the progeny generated by these Fezf2 positive neural precursors. Gene expression analysis indicates that Fezf2 positive cells give rise to deep and superficial layer projection neurons, as well as glia, while Fezf2 negative cells give rise to other neural subtypes and cells expressing eye-associated markers. Through timing and FACS purification we were able to generate a population of post -mitotic neurons that were 94% Fezf2 positive, many of which co-expressed additional markers of deep-layer projection neurons. Finally, Fezf2 positive cells transplanted into neonatal mice were able to maintain Fezf2 expression, adopted pyramidal morphologies, and were able to correctly project down appropriate subcerebral motor pathways, even reaching the pyramidal decussation and the spinal cord.Additionally presented here is the development and implementation of two BAC constructs for use in permanently labeling populations of hESCs and their progeny

The surgical guidelines for male breast cancer (MBC) have been largely guided by female-predominant clinical trials. Because no clinical trial has been conducted to examine the surgical treatment of MBC, we performed a systematic review comparing the survival of patients with MBC who had undergone breast conserving surgery (BCS) and those who had undergone mastectomy and evaluated the patients' radiotherapy compliance after BCS. We performed a systematic search of electronic databases to find MBC cohort studies that had reported ≥ 1 survival outcome (disease-free survival [DFS], disease-specific survival [DSS], or overall survival [OS]) stratified by surgical treatment (BCS and/or mastectomy) and/or radiotherapy compliance with BCS. A total of 1 prospective and 9 retrospective cohort studies were included, with the number of patients ranging from 7 to 6039. Of the BCS patients, compliance with postoperative radiotherapy was low (range, 27%-46%), with the exception of 1 single-institution prospective study that reported 86% compliance (6 of 7 patients). The pooled estimate for all patients with MBC was 83% (95% confidence interval [CI], 78%-88%) for 5-year DSS and 66% (95% CI, 63%-70%) for 5-year OS. Most studies reported no differences in DFS, DSS, or OS for BCS and mastectomy. BCS is a reasonable treatment approach for MBC because it was associated with oncologic outcomes similar to those with mastectomy. However, the low rates of radiotherapy compliance among male patients who underwent BCS is concerning and highlights the importance of shared decision-making with patients with MBC when selecting a surgical treatment strategy.

Introduction

Low distal aortic flow via partial aortic occlusion (AO) may mitigate ischemia induced by resuscitative endovascular balloon occlusion of the aorta (REBOA). We compared endocrine effects of a novel simulated partial AO strategy, endovascular variable aortic control (EVAC), with simulated REBOA in a swine model.

Materials and methods

Aortic flow in 20 swine was routed from the supraceliac aorta through an automated extracorporeal circuit. Following liver injury-induced hemorrhagic shock, animals were randomized to control (unregulated distal flow), simulated REBOA (no flow, complete AO), or simulated EVAC (distal flow of 100-300 mL/min after 20 minutes of complete AO). After 90 minutes, damage control surgery, resuscitation, and full flow restoration ensued. Critical care was continued for 4.5 hours or until death.

Results

Serum angiotensin II concentration was higher in the simulated EVAC (4,769 ± 624 pg/mL) than the simulated REBOA group (2649 ± 429) (p = 0.01) at 180 minutes. There was no detectable difference in serum renin [simulated REBOA: 231.3 (227.9-261.4) pg/mL; simulated EVAC: 294.1 (231.2-390.7) pg/mL; p = 0.27], aldosterone [simulated EVAC: 629 (454-1098), simulated REBOA: 777 (575-1079) pg/mL, p = 0.53], or cortisol (simulated EVAC: 141 ± 12, simulated REBOA: 127 ± 9 ng/mL, p = 0.34) concentrations between groups.

Conclusions

Simulated EVAC was associated with higher serum angiotensin II, which may have contributed to previously reported cardiovascular benefits. Future studies should evaluate the renal effects of EVAC and the concomitant therapeutic use of angiotensin II.

Background

Current treatment guidelines for male breast cancer are predominantly guided by female-only clinical trials. With scarce research, it is unclear whether breast-conserving therapy (BCT) is equivalent to mastectomy in men. We sought to compare overall survival (OS) among male breast cancer patients who underwent BCT versus mastectomy.

Methods

We performed a retrospective analysis of 8445 stage I-II (T1-2 N0-1 M0) male breast cancer patients from the National Cancer Database (2004-2014). Patients were grouped according to surgical and radiation therapy (RT). BCT was defined as partial mastectomy followed by RT. Multivariable and inverse probability of treatment-weighted (IPTW) Cox proportional hazards models were used to compare OS between treatment groups, controlling for demographic and clinicopathologic characteristics.

Results

Most patients underwent total mastectomy (61.2%), whereas 18.2% underwent BCT, 12.4% underwent total mastectomy with RT, and 8.2% underwent partial mastectomy alone. In multivariable and IPTW models, partial mastectomy alone, total mastectomy alone, and total mastectomy with RT were associated with worse OS compared with BCT (p < 0.001 all). Ten-year OS was 73.8% for BCT and 56.3, 58.0 and 56.3% for other treatment approaches. Older age, higher T/N stage, histological grade, and triple-negative receptor status were associated with poorer OS (p < 0.05). Subgroup analysis by stage demonstrated similar results.

Conclusions

In this national sample of male breast cancer patients, BCT was associated with greater survival. The underlying mechanisms of this association warrant further study, because more routine adoption of BCT in male breast cancer appears to translate into clinically meaningful improvements in survival.

Background

The duration of use and efficacy of resuscitative endovascular balloon occlusion of the aorta (REBOA) is limited by distal ischemia. We developed a hybrid endovascular-extracorporeal circuit variable aortic control (VAC) device to extend REBOA duration in a lethal model of hemorrhagic shock to serve as an experimental surrogate to further the development of endovascular VAC (EVAC) technologies.

Methods

Nine Yorkshire-cross swine were anesthetized, instrumented, splenectomized, and subjected to 30% liver amputation. Following a short period of uncontrolled hemorrhage, REBOA was instituted for 20 minutes. Automated variable occlusion in response to changes in proximal mean arterial pressure was applied for the remaining 70 minutes of the intervention phase using the automated extracorporeal circuit. Damage-control surgery and whole blood resuscitation then occurred, and the animals were monitored for a total of 6 hours.

Results

Seven animals survived the initial surgical preparation. After 20 minutes of complete REBOA, regulated flow was initiated through the extracorporeal circuit to simulate VAC and provide perfusion to distal tissue beds during the 90-minute intervention phase. Two animals required circuit occlusion for salvage, while five animals tolerated sustained, escalating restoration of distal blood flow before surgical hemorrhage control. Animals tolerating distal flow had preserved renal function, maintained proximal blood pressure, and rapidly weaned from complete REBOA.

Conclusion

We combined a novel automated, extracorporeal circuit with complete REBOA to achieve EVAC in a swine model of uncontrolled hemorrhage. Our approach regulated proximal aortic pressure, alleviated supranormal values above the balloon, and provided controlled distal aortic perfusion that reduced ischemia without inducing intolerable bleeding. This experimental model serves as a temporary surrogate to guide future EVAC catheter designs that may provide transformational approaches to hemorrhagic shock.

Here, we report that the LynB splice variant of the Src-family kinase Lyn exerts a dominant immunosuppressive function in vivo, whereas the LynA isoform is uniquely required to restrain autoimmunity in female mice. We used CRISPR-Cas9 gene editing to constrain lyn splicing and expression, generating single-isoform LynA knockout (LynA^KO) or LynB^KO mice. Autoimmune disease in total Lyn^KO mice is characterized by production of antinuclear antibodies, glomerulonephritis, impaired B cell development, and overabundance of activated B cells and proinflammatory myeloid cells. Expression of LynA or LynB alone uncoupled the developmental phenotype from the autoimmune disease: B cell transitional populations were restored, but myeloid cells and differentiated B cells were dysregulated. These changes were isoform-specific, sexually dimorphic, and distinct from the complete Lyn^KO. Despite the apparent differences in disease etiology and penetrance, loss of either LynA or LynB had the potential to induce severe autoimmune disease with parallels to human systemic lupus erythematosus (SLE).

Large-scale changes in global climate at the end of the Pleistocene significantly impacted ecosystems across North America. However, the pace and scale of biotic turnover in response to both the Younger Dryas cold period and subsequent Holocene rapid warming have been challenging to assess because of the scarcity of well dated fossil and pollen records that covers this period. Here we present an ancient DNA record from Hall's Cave, Texas, that documents 100 vertebrate and 45 plant taxa from bulk fossils and sediment. We show that local plant and animal diversity dropped markedly during Younger Dryas cooling, but while plant diversity recovered in the early Holocene, animal diversity did not. Instead, five extant and nine extinct large bodied animals disappeared from the region at the end of the Pleistocene. Our findings suggest that climate change affected the local ecosystem in Texas over the Pleistocene-Holocene boundary, but climate change on its own may not explain the disappearance of the megafauna at the end of the Pleistocene.

Functional MRI (fMRI) data acquired using echo-planar imaging (EPI) are highly distorted by magnetic field inhomogeneities. Distortion and differences in image contrast between EPI and T1-weighted and T2-weighted (T1w/T2w) images makes their alignment a challenge. Typically, field map data are used to correct EPI distortions. Alignments achieved with field maps can vary greatly and depends on the quality of field map data. However, many public datasets lack field map data entirely. Additionally, reliable field map data is often difficult to acquire in high-motion pediatric or developmental cohorts. To address this, we developed Synth, a software package for distortion correction and cross-modal image registration that does not require field map data. Synth combines information from T1w and T2w anatomical images to construct an idealized undistorted synthetic image with similar contrast properties to EPI data. This synthetic image acts as an effective reference for individual-specific distortion correction. Using pediatric (ABCD: Adolescent Brain Cognitive Development) and adult (MSC: Midnight Scan Club; HCP: Human Connectome Project) data, we demonstrate that Synth performs comparably to field map distortion correction approaches, and often outperforms them. Field map-less distortion correction with Synth allows accurate and precise registration of fMRI data with missing or corrupted field map information.

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.