Buffering Mechanism in Aortic Arch Artery Formation and Congenital Heart Disease.

Background: The resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease arising from defective morphogenesis of pharyngeal arch arteries (PAAs) and their derivatives.

Methods: Mouse genetics, lineage tracing, confocal microscopy, and quantitative image analyses were used to investigate mechanisms of PAA formation and repair.

Stratification of Patients with Renal Cell Carcinoma by the Abundance of Sarcomatoid Features Reveals Differences in Survival and the Underlying Pathobiology.

Sarcomatoid renal cell carcinoma (sRCC) is histologically heterogeneous, with variable sarcomatoid amounts intermixed within epithelial carcinoma. However, the current classification for this aggressive disease is homogeneous and agnostic to the sarcomatoid proportion. We investigated whether sRCC subclassification has prognostic value and can reveal the biology underlying dedifferentiation and its clinical aggressiveness.

Hypoglossal nerve stimulation over-titration.

Unlabelled: This case report reviews worsening obstructive sleep apnea (OSA) events in a patient over-titrated with a hypoglossal nerve stimulator. A healthy 57-year-old man underwent hypoglossal nerve stimulator implantation for moderate OSA. During an in-laboratory hypoglossal nerve stimulator titration the patient had improvement of his OSA at 2.

Androgen deprivation triggers a cytokine signaling switch to induce immune suppression and prostate cancer recurrence.

Androgen deprivation therapy (ADT) is an effective but not curative treatment for advanced and recurrent prostate cancer (PC). We investigated the mechanisms controlling the response to androgen-deprivation by surgical castration in genetically-engineered mouse models (GEMM) of PC, using high frequency ultrasound imaging to rigorously measure tumor volume. Castration initially causes almost all tumors to shrink in volume, but many tumors subsequently recur within 5-10 weeks.

Identification of novel buffering mechanisms in aortic arch artery development and congenital heart disease.

Rationale: The resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease (CHD) arising from defective morphogenesis of pharyngeal arch arteries (PAA) and their derivatives.

Objective: To uncover mechanisms underlying the robustness of PAA morphogenesis.

CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity.

Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism.

Rate of castration-induced prostate stroma regression is reduced in a mouse model of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease producing lower urinary tract symptoms related to the resulting enlarged prostate. BPH is pathologically characterized by hyperplastic growth in both epithelial and stromal compartments. Androgen signaling is essential for prostate function and androgen blockade is the second-line medical therapy to relieve symptoms of BPH.

Universal logic with encoded spin qubits in silicon.

Quantum computation features known examples of hardware acceleration for certain problems, but is challenging to realize because of its susceptibility to small errors from noise or imperfect control. The principles of fault tolerance may enable computational acceleration with imperfect hardware, but they place strict requirements on the character and correlation of errors. For many qubit technologies, some challenges to achieving fault tolerance can be traced to correlated errors arising from the need to control qubits by injecting microwave energy matching qubit resonances.

Combined BRCA2 and MAGEC3 Expression Predict Outcome in Advanced Ovarian Cancers.

Like BRCA2, MAGEC3 is an ovarian cancer predisposition gene that has been shown to have prognostic significance in ovarian cancer patients. Despite the clinical significance of each gene, no studies have been conducted to assess the clinical significance of their combined expression. We therefore sought to determine the relationship between MAGEC3 and BRCA2 expression in ovarian cancer and their association with patient characteristics and outcomes.

Mitigating the prevalence and function of myeloid-derived suppressor cells by redirecting myeloid differentiation using a novel immune modulator.

Background: Immune suppression is common in neoplasia and a major driver is tumor-induced myeloid dysfunction. Yet, overcoming such myeloid cell defects remains an untapped strategy to reverse suppression and improve host defense. Exposure of bone marrow progenitors to heightened levels of myeloid growth factors in cancer or following certain systemic treatments promote abnormal myelopoiesis characterized by the production of myeloid-derived suppressor cells (MDSCs) and a deficiency in antigen-presenting cell function.

Estrogen Receptor-Beta2 (ERβ2)-Mutant p53-FOXM1 Axis: A Novel Driver of Proliferation, Chemoresistance, and Disease Progression in High Grade Serous Ovarian Cancer (HGSOC).

High grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of epithelial ovarian cancer. Prevalence (~96%) of mutant p53 is a hallmark of HGSOC. Estrogen receptor-beta (ERβ) has been reported to be another important player in HGSOC, although the pro-versus anti-tumorigenic role of its different isoforms remains unsettled.

CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities.

Progression through G1/S phase of the cell cycle is coordinated by cyclin-dependent kinase (CDK) activities. Here, we find that the requirement for different CDK activities and cyclins in driving cancer cell cycles is highly heterogeneous. The differential gene requirements associate with tumor origin and genetic alterations.

VSSP abrogates murine ovarian tumor-associated myeloid cell-driven immune suppression and induces M1 polarization in tumor-associated macrophages from ovarian cancer patients.

The ovarian tumor microenvironment (TME) is characterized by the accumulation of immunosuppressive tumor-associated macrophages (TAMs) and granulocytic cells. Very small size particles (VSSP), comprised of the ganglioside NAcGM3 and Neisseria meningitidis derived outer membrane vesicles, is being developed as a nanoparticulated modulator of innate immunity. Prior studies have shown that VSSP enhanced antigen-specific cytotoxic T cell responses and reduced the suppressive phenotype of splenic granulocytic cells in tumor-bearing mice.

Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers.

Rare variants in MAGEC3 are associated with BRCA negative, early-onset ovarian cancers. Given this association, we evaluated the impact of MAGEC3 protein expression on prognosis and transcription. We quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in = 394 advanced ovarian cancers, assessed the correlation of these values with clinicopathologic and immunological features and modeled survival using univariate and multivariate models.

Retrospective review of pyrocarbon radial head replacement.

Background: Radial head arthroplasty is the preferred surgical management for complex, unreconstructable radial head fractures. There has been increasing use of pyrocarbon prostheses, with potential tribology and modulus advantages over metallic counterparts. This study aims to assess clinical and radiological outcomes for radial head replacement after trauma using a modular, uncemented pyrocarbon prosthesis.

Selective therapeutic strategy for p53-deficient cancer by targeting dysregulation in DNA repair.

Breast carcinomas commonly carry mutations in the tumor suppressor p53, although therapeutic efforts to target mutant p53 have previously been unfruitful. Here we report a selective combination therapy strategy for treatment of p53 mutant cancers. Genomic data revealed that p53 mutant cancers exhibit high replication activity and express high levels of the Base-Excision Repair (BER) pathway, whereas experimental testing showed substantial dysregulation in BER.

Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer.

T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression.

USP1 Regulates TAZ Protein Stability Through Ubiquitin Modifications in Breast Cancer.

The Hippo signaling pathway is an evolutionarily conserved pathway that was initially discovered in and was later found to have mammalian orthologues. The key effector proteins in this pathway, YAP/TAZ, are often dysregulated in cancer, leading to a high degree of cell proliferation, migration, metastasis and cancer stem cell populations. Due to these malignant phenotypes it is important to understand the regulation of YAP/TAZ at the protein level.

Percutaneous Cryoablation of Recurrent Pancreatic Mass for Life-Threatening Pancreatic VIPoma Syndrome: A Case Report.

We present the case of a 73-year-old female who underwent percutaneous cryoablation for recurrent life-threatening pancreatic vasoactive intestinal polypeptide-producing tumor (VIPoma) following a pancreaticoduodenectomy and chemotherapy 5 years earlier. She presented with profuse watery diarrhea causing severe electrolyte and acid-base abnormalities, along with acute kidney injury. Cryoablation was successful in treating her profound symptoms, completely reversing her clinical course.

Functional Dart-Throwing Motion: A Clinical Comparison of Four-Corner Fusion to Radioscapholunate Fusion Using Inertial Motion Capture.

 Dart-throwing motion (DTM) is an important functional arc of the wrist from radial extension to ulna flexion. An aim of partial fusion surgery of the wrist is to maintain maximal functional motion while addressing the pathology. The radioscapholunate (RSL) fusion, accompanied with partial resection of the distal scaphoid, is thought to allow better DTM than other partial wrist fusions such as the four-corner fusion (4CF).

Non-invasive ventilation in patients with an altered level of consciousness. A clinical review and practical insights.

Non-invasive ventilation has gained an increasingly pivotal role in the treatment of acute hypoxemic and/or hypercapnic respira-tory failure and offers multiple advantages over invasive mechanical ventilation. Some of these advantages include the preserva-tion of airway defense mechanisms, a reduced need for sedation, and an avoidance of complications related to endotracheal intubation. Despite its advantages, non-invasive ventilation has some contraindications that include, among them, severe encephalopathy.

Clonality and antigen-specific responses shape the prognostic effects of tumor-infiltrating T cells in ovarian cancer.

CD8 tumor-infiltrating lymphocytes (TILs) are not all specific for tumor antigens, but can include bystander TILs that are specific for cancer-irrelevant epitopes, and it is unknown whether the T-cell repertoire affects prognosis. To delineate the complexity of anti-tumor T-cell responses, we utilized a computational method for assembly of sequences from CDR3 regions of 369 high-grade serous ovarian cancers from TCGA, and then applied deep TCR-sequencing for analyses of paired tumor and peripheral blood specimens from an independent cohort of 99 ovarian cancer patients. Strongly monoclonal T-cell repertoires were associated with favorable prognosis (PFS, HR = 0.