Heterozygous PRKN mutations are common but do not increase the risk of Parkinson's disease.

PRKN mutations are the most common recessive cause of Parkinson's disease and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients at the population scale, however, remains a challenge, as roughly half are copy number variants and many single nucleotide polymorphisms are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN mutations has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in two cohorts with near complete genotyping of both single nucleotide polymorphisms and copy number variants: the NIH-PD + AMP-PD cohort, the largest Parkinson's disease case-control cohort with whole genome sequencing data from 4094 participants, and the UK Biobank, the largest cohort study with whole exome sequencing and genotyping array data from 200 606 participants. Using the NIH-PD participants, who were genotyped using whole genome sequencing, genotyping array, and multi-plex ligation-dependent probe amplification, we validated genotyping array for the detection of copy number variants. Additionally, in the NIH-PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and suggested that cryptic loss of function variants in monoallelic carriers are not a substantial confounder for association studies. In the UK Biobank, we identified 2692 PRKN copy number variants from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exon 2 accounted for roughly half of all copy number variants and the vast majority (88%) involved exons 2, 3, or 4. In the UK Biobank, we found a pathogenic PRKN mutation in 1.8% of participants and two mutations in ∼1/7800 participants. Those with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 0.91 (0.58-1.38), P-value 0.76] or a parent with Parkinson's disease [odds ratio = 1.12 (0.94-1.31), P-value = 0.19]. Similarly, those in the NIH-PD + AMP + PD cohort with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 1.29 (0.74-2.38), P-value = 0.43]. Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of Parkinson's disease.

Novel Dormancy Mechanism of Castration Resistance in Bone Metastatic Prostate Cancer Organoids.

Advanced prostate cancer (PCa) patients with bone metastases are treated with androgen pathway directed therapy (APDT). However, this treatment invariably fails and the cancer becomes castration resistant. To elucidate resistance mechanisms and to provide a more predictive pre-clinical research platform reflecting tumor heterogeneity, we established organoids from a patient-derived xenograft (PDX) model of bone metastatic prostate cancer, PCSD1. APDT-resistant PDX-derived organoids (PDOs) emerged when cultured without androgen or with the anti-androgen, enzalutamide. Transcriptomics revealed up-regulation of neurogenic and steroidogenic genes and down-regulation of DNA repair, cell cycle, circadian pathways and the severe acute respiratory syndrome (SARS)-CoV-2 host viral entry factors, ACE2 and TMPRSS2. Time course analysis of the cell cycle in live cells revealed that enzalutamide induced a gradual transition into a reversible dormant state as shown here for the first time at the single cell level in the context of multi-cellular, 3D living organoids using the Fucci2BL fluorescent live cell cycle tracker system. We show here a new mechanism of castration resistance in which enzalutamide induced dormancy and novel basal-luminal-like cells in bone metastatic prostate cancer organoids. These PDX organoids can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry.

α-Synuclein Deposition in Sympathetic Nerve Fibers in Genetic Forms of Parkinson's Disease.

BACKGROUND: Cytoplasmic inclusions of α-synuclein (α-syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails α-syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of α-syn have not been reported. OBJECTIVE: This cross-sectional observational study compared magnitudes of intraneuronal deposition of α-syn in common and rare genetic forms of PD. METHODS: α-Syn deposition was quantified by the α-syn-tyrosine hydroxylase colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (n = 3), PRKN [biallelic (n = 7) and monoallelic (n = 3)], LRRK2 (n = 7), GBA (n = 7), or PARK7/DJ1 [biallelic (n = 1) and monoallelic (n = 2)]. Twenty-five of the mutation carriers had PD and five did not. Data were also analyzed from 19 patients with idiopathic PD and 16 control participants. RESULTS: α-Syn deposition varied as a function of genotype (F = 16.7, P < 0.0001). It was above the control range in 100% of subjects with SNCA mutations, 100% with LRRK2 mutations, 95% with idiopathic PD, 83% with GBA mutations, and 0% with biallelic PRKN mutations. α-Syn deposition in the biallelic PRKN group was significantly higher than in the control group. In addition, patients with biallelic PRKN mutations had higher α-syn deposition than their unaffected siblings. CONCLUSIONS: Individuals with SNCA, DJ-1, LRRK2, or GBA mutations have substantial intraneuronal α-syn deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. Biallelic PRKN patients may have mildly increased α-syn deposition compared with control subjects. © 2021 International Parkinson and Movement Disorder Society.

The Influence of Patient Exposure to Breast Reconstruction Approaches and Education on Patient Choices in Breast Cancer Treatment.

BACKGROUND: The landscape of surgical and medical management and patient choices for breast cancer treatment changes as breast reconstruction and oncoplastic approaches improve and diversify. Increased access to breast reconstruction, in addition to patient education, influences the breast cancer patient. Therefore, the examination of the possible impact of reconstructive surgery on all stages of the breast cancer management per se seemed timely. METHODS: Plastic surgery consults were arranged for 520 new patients diagnosed with breast cancer (2012-2016) including patients with noninvasive breast cancer but at high risk of further cancer development. To test the plastic surgery impact on patient choices regarding the management of the cancer, a subset of 90 patients was identified to test the plastic surgery impact on patient choices. These patients were referred to plastic surgery, following the first round of consultations by surgical and medical oncologists with only the preliminary oncological management plan defined. After a plastic surgery consultation, but prior to finalization of the overall oncological management plan, they were surveyed on the subject of modification of their personal choices and requests pertaining to their cancer management. RESULTS: In this subset of 90 patients 40 (44%) returned to their surgical or medical oncologist considering changes of the primary management plan after their plastic surgery consultation. Twenty-six (28%) ultimately altered their plan, and the following patient-driven changes were made: mastectomy as opposed to lumpectomy (18 patients [20%]), contralateral prophylactic mastectomy (11 patients [12%]), nipple/areola removal as opposed to nipple/areola sparing suggested by the oncologists (5 patients [6%]), oncoplastic breast reduction as part of lumpectomy (5 patients [6%]), and other modifications (3 patients [3%]). CONCLUSIONS: Decisions for altering the preliminary oncologic plan or choosing a specific alternative (eg, lumpectomy plus radiation vs mastectomy) resulted from patient education on (1) reconstructive options, (2) aesthetic pitfalls and results. and (3) their interfacing with the oncological outcomes. Ultimately, plastic surgeons influence the multispecialty breast cancer management and patient decision-making process. Therefore, oncological literacy for plastic surgeons is essential to provide state-of-the-art breast cancer care and avoidance of suboptimal patient decisions.

The Cost to Attending Surgeons of Resident Involvement in Academic Hand Surgery.

PURPOSE: For many types of surgical cases, there is an increase in length with the participation of a resident physician. The lost operative time productivity is not necessarily mitigated in any fashion other than to benefit the experience of the trainee. Moreover, increasing pressures to maximize productivity, coupled with diminishing reimbursements serve to disincentive resident involvement. The aim of this study was to examine the opportunity cost in the academic setting for intraoperative resident participation during specific hand surgery cases. METHODS: Retrospective analysis was performed on the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) database from 2006 to 2015. Cases were identified by Current Procedural Terminology code to isolate distal radius fracture repairs, carpal tunnel releases, scaphoid fractures repairs, and metacarpal fracture repairs. Variables collected included operation time, presence or absence of resident physician, and postgraduate year level. Statistical analysis was performed using the statistical computing software R 3.4.2 (R Foundation for Statistical Computing, Vienna, Austria). Cost analysis was performed to quantify the effect of operative times in terms of relative value units (RVUs) lost. RESULTS: A total of 3727 cases were identified. Of those, 1264 cases were performed with a resident present. Residents participated in cases with higher total RVU (14.91 vs 13.16, P < 0.001). There was a statistically significant increase of 24.3 minutes (P < 0.001) in the mean operation time with a resident present as compared with those without. Moreover, RVU per hour in resident cases was significantly lower by 2.97 RVU per hour or 21% (P < 0.001). Using the late 2018 Medicare physician conversion factor of US $33.9996, the opportunity cost to attending physicians is US $159.20 per case. CONCLUSIONS: Resident participation in surgical cases is paramount to the education of future trainees, particularly in the era of trainee duty hour reform. Because residents are participating in higher total RVU cases, this selection bias may be playing a role in explaining our result. Nonetheless, resident involvement for certain procedures comes at an opportunity cost to faculty surgeons. How to balance the cost to train residents in the emerging value-based health systems will prove to be challenging but requires consideration.

A Novel Method for Quantifying Intracranial Volume Change by Distraction Osteogenesis for Craniosynostosis.

INTRODUCTION: Methods of reporting quantitative results for distraction osteogenesis (DO) of craniosynostosis have been inconsistent. Therefore, the efficacy of differing techniques and timing in regard to volume change is not well established, with no uniform metric for comparisons. Given that cranial vault remodeling with DO may be completed with different approaches, analysis was made to determine (1) the relative efficiency of different approaches in expanding intracranial volume (ICV) and (2) the impact of adjusting for ICV growth on measured DO efficiency. METHODS: Patients with craniosynostosis were treated with open cranial vault reconstruction combined with internal distraction. Preoperative and postoperative computed tomography scans were used to quantify ICV change. The metric was determined by dividing percent ICV change by total distraction length. The metric was used as a proxy for efficiency to compare posterior and anterior distraction between groups using the Mann-Whitney U test and within a subgroup of patients who underwent 2-stage distraction using the Wilcoxon matched-pairs signed rank test. RESULTS: Twenty patients underwent cranial vault remodeling with DO: 14 unicoronal, 3 bicoronal, 2 multisutural, and 1 lambdoid. Results are reported in medians. Distraction efficiency was 0.99%/mm for primary anterior, unilateral distraction for unicoronal patients (n = 13, aged 9.1 months) and 4.28%/mm for posterior distraction using multiple distractors (n = 4, aged 6.3 months). In terms of the metric, primary posterior distraction was significantly more efficient than primary anterior distraction (P = 0.007). Three patients who had undergone primary posterior distraction later underwent secondary anterior distraction. Again, posterior distraction was shown to be significantly more efficient (5.16 vs 0.62, P = 0.050). For the unicoronal patients who received anterior unilateral distraction, an adjusted metric was calculated to account for normal intracranial growth. This was found to be 0.39%/mm, which was significantly different from the unadjusted metric (P = 0.0001). CONCLUSIONS: Posterior distraction is more efficient for ICV expansion than anterior distraction, which may have implications for the choice of approach for craniosynostosis repair. In addition, this is the first report of a novel standardized metric for analyzing ICV change achieved by DO. This tool allows for adjusting the efficiency metric for expected ICV growth, which significantly impacts its value.

Moving Parkinson care to the home.

In many ways, the care of individuals with Parkinson disease does not meet their needs. Despite the documented benefits of receiving care from clinicians with Parkinson disease expertise, many patients (if not most) do not. Moreover, current care models frequently require older individuals with impaired mobility, cognition, and driving ability to be driven by overburdened caregivers to large, complex urban medical centers. Moving care to the patient's home would make Parkinson disease care more patient-centered. Demographic factors, including aging populations, and social factors, such as the splintering of the extended family, will increase the need for home-based care. Technological advances, especially the ability to assess and deliver care remotely, will enable the transition of care back to the home. However, despite its promise, this next generation of home-based care will have to overcome barriers, including outdated insurance models and a technological divide. Once these barriers are addressed, home-based care will increase access to high quality care for the growing number of individuals with Parkinson disease. © 2016 International Parkinson and Movement Disorder Society.

Alternative splicing networks regulated by signaling in human T cells.

The formation and execution of a productive immune response requires the maturation of competent T cells and a robust change in cellular activity upon antigen challenge. Such changes in cellular function depend on regulated alterations to protein expression. Previous research has focused on defining transcriptional changes that regulate protein expression during T-cell maturation and antigen stimulation. Here, we globally analyze another critical process in gene regulation during T-cell stimulation, alternative splicing. Specifically, we use RNA-seq profiling to identify 178 exons in 168 genes that exhibit robust changes in inclusion in response to stimulation of a human T-cell line. Supporting an important role for the global coordination of alternative splicing following T-cell stimulation, these signal-responsive exons are significantly enriched in genes with functional annotations specifically related to immune response. The vast majority of these genes also exhibit differential alternative splicing between naive and activated primary T cells. Comparison of the responsiveness of splicing to various stimuli in the cultured and primary T cells further reveals at least three distinct networks of signal-induced alternative splicing events. Importantly, we find that each regulatory network is specifically associated with distinct sequence features, suggesting that they are controlled by independent regulatory mechanisms. These results thus provide a basis for elucidating mechanisms of signal pathway-specific regulation of alternative splicing during T-cell stimulation.

A variable precision covering-based rough set model based on functions.

Classical rough set theory is a technique of granular computing for handling the uncertainty, vagueness, and granularity in information systems. Covering-based rough sets are proposed to generalize this theory for dealing with covering data. By introducing a concept of misclassification rate functions, an extended variable precision covering-based rough set model is proposed in this paper. In addition, we define the f-lower and f-upper approximations in terms of neighborhoods in the extended model and study their properties. Particularly, two coverings with the same reductions are proved to generate the same f-lower and f-upper approximations. Finally, we discuss the relationships between the new model and some other variable precision rough set models.

Matroidal structure of generalized rough sets based on tolerance relations.

Rough set theory provides an effective tool to deal with uncertain, granular, and incomplete knowledge in information systems. Matroid theory generalizes the linear independence in vector spaces and has many applications in diverse fields, such as combinatorial optimization and rough sets. In this paper, we construct a matroidal structure of the generalized rough set based on a tolerance relation. First, a family of sets are constructed through the lower approximation of a tolerance relation and they are proved to satisfy the circuit axioms of matroids. Thus we establish a matroid with the family of sets as its circuits. Second, we study the properties of the matroid including the base and the rank function. Moreover, we investigate the relationship between the upper approximation operator based on a tolerance relation and the closure operator of the matroid induced by the tolerance relation. Finally, from a tolerance relation, we can get a matroid of the generalized rough set based on the tolerance relation. The matroid can also induce a new relation. We investigate the connection between the original tolerance relation and the induced relation.

Salience Interest Option: Temporal abstraction with salience interest functions.

Reinforcement Learning (RL) is a significant machine learning subfield that emphasizes learning actions based on environment to obtain optimal behavior policy. RL agents can make decisions at variable time scales in the form of temporal abstractions, also known as options. The issue of discovering options has seen a considerable research effort. Most notably, the Interest Option Critic (IOC) algorithm first extends the initial set to the interest function, providing a method for learning options specialized to certain state space regions. This approach offers a specific attention mechanism for action selection. Unfortunately, this method still suffers from the classic issues of poor data efficiency and lack of flexibility in RL when learning options end-to-end through backpropagation. This paper proposes a new approach called Salience Interest Option Critic (SIOC), which chooses subsets of existing initiation sets for RL. Specifically, these subsets are not learned by backpropagation, which is slow and tends to overfit, but through particle filters. This approach enables the rapid and flexible identification of critical subsets using only reward feedback. We conducted experiments in discrete and continuous domains, and our proposed method demonstrate higher efficiency and flexibility than other methods. The generated options are more valuable within a single task and exhibited greater interpretability and reusability in multi-task learning scenarios.

A rare non-gadolinium enhancing sarcoma brain metastasis with microenvironment dominated by tumor-associated macrophages.

Brain metastases occur in 1% of sarcoma cases and are associated with a median overall survival of 6 months. We report a rare case of a brain metastasis with unique radiologic and histopathologic features in a patient with low grade fibromyxoid sarcoma (LGFMS) previously treated with immune checkpoint inhibitor (ICI) therapy. The lone metastasis progressed in the midbrain tegmentum over 15 months as a non-enhancing, T2-hyperintense lesion with peripheral diffusion restriction, mimicking a demyelinating lesion. Histopathology of the lesion at autopsy revealed a rich infiltrate of tumor-associated macrophages (TAMs) with highest density at the leading edge of the metastasis, whereas there was a paucity of lymphocytes, suggestive of an immunologically cold environment. Given the important immunosuppressive and tumor-promoting functions of TAMs in gliomas and carcinoma/melanoma brain metastases, this unusual case provides an interesting example of a dense TAM infiltrate in a much rarer sarcoma brain metastasis.

Generalized vestibular hyporeflexia and chronic upbeat nystagmus due to thiamine deficiency.

BACKGROUND: Ocular motor and vestibular manifestations of Wernicke's thiamine deficiency (WTD) are frequent and heterogeneous. Previous neuropathological and neuroimaging findings identified brainstem and cerebellar lesions responsible for these findings, however, peripheral vestibular lesions are probably uncommon in human WTD, though noted on an avian thiamine deficient study. MATERIAL: Single case study of a WTD patient post-gastric bypass who developed ataxia, oscillopsia and nystagmus, with low serum thiamine, and increased MRI T2 signal in the thalami, but normal brainstem and cerebellum. Vestibular evaluation showed significant vestibular hyporreflexia affecting all six canals, and a chronic upbeat nystagmus, now for 14 months after WTD onset. METHODS: Serial clinical, video head impulse, nystagmus analysis, cervical and ocular vestibular evoked responses. She is undergoing treatment with Memantine, Clonazepam and vestibular rehabilitation, and feels improvement. CONCLUSION: This report shows a novel combination of central and peripheral vestibular findings, of relevance for diagnosis and treatment, in addition to the development of a coherent hypothesis on the ocular motor and vestibular findings in WTD.

Liquid Biopsy Screening for Early Detection of Lung Cancer: Current State and Future Directions.

Liquid biopsy (LB) is clinically utilized to detect minute amounts of genetic material or protein shed by cancer cells, most commonly cell free DNA (cfDNA), as a noninvasive precision oncology tool to assess genomic alterations to guide cancer therapy or to detect the persistence of tumor cells after therapy. LB is also being developed as a multi-cancer screening assay. The use of LB holds great promise as a tool to detect lung cancer early. Although lung cancer screening (LCS) with low-dose computed tomography (LDCT) substantially reduces lung cancer mortality in high-risk individuals, the ability of current LCS guidelines to reduce the public health burden of advanced lung cancer through early detection has been limited. LB may be an important tool to improve early lung cancer detection among all populations at risk for lung cancer. In this systematic review, we summarize the test characteristics, including sensitivity and specificity of individual tests, as they pertain to the detection of lung cancer.  We also address critical questions in the use of liquid biopsy for early detection of lung cancer including: 1. How might liquid biopsy be used to detect lung cancer early; 2. How accurate is liquid biopsy in detecting lung cancer early; and 3. Does liquid biopsy perform as well in never and light-smokers compared with current and former smokers.

Learning matrix factorization with scalable distance metric and regularizer.

Matrix factorization has always been an encouraging field, which attempts to extract discriminative features from high-dimensional data. However, it suffers from negative generalization ability and high computational complexity when handling large-scale data. In this paper, we propose a learnable deep matrix factorization via the projected gradient descent method, which learns multi-layer low-rank factors from scalable metric distances and flexible regularizers. Accordingly, solving a constrained matrix factorization problem is equivalently transformed into training a neural network with an appropriate activation function induced from the projection onto a feasible set. Distinct from other neural networks, the proposed method activates the connected weights not just the hidden layers. As a result, it is proved that the proposed method can learn several existing well-known matrix factorizations, including singular value decomposition, convex, nonnegative and semi-nonnegative matrix factorizations. Finally, comprehensive experiments demonstrate the superiority of the proposed method against other state-of-the-arts.

Free functional muscle transfer for lower extremity reconstruction.

BACKGROUND: Free functional muscle transfer is a reconstructive strategy for the reconstruction of lost muscle units in the lower extremity after oncologic resection, trauma, compartment syndrome, or severe nerve injuries. Under appropriate circumstances, free functional muscle transfer may be the only suitable reconstructive option. This article reviews the underlying principles of free functional muscle transfer, its application to lower extremity reconstruction, appropriate patient selection, and surgical techniques. METHODS: The underlying principles of free functional muscle transfer, its application to lower extremity reconstruction, appropriate patient selection, and surgical techniques are presented. Commonly used donor muscles appropriate for each type of functional defect are discussed. A review of recent publications on free functional muscle transfer in the lower extremity was also performed. RESULTS: Good functional recovery with a Medical Research Council grade of up to 4/5 and full range of motion can be attained with free functional muscle transfer. Clinical outcomes and specific parameters for published case series in lower extremity free functional muscle transfer are presented and an illustrative case. CONCLUSION: Free functional muscle transfer is a suitable treatment for the appropriate patient to restore essential functions and potentially regain ambulation. However, additional published clinical outcomes are needed and represent a major area for further investigation.

Patient reported outcomes and treatment satisfaction in patients with cushing syndrome.

PURPOSE: Cushing Syndrome (CS) is a rare endocrine disorder associated with physical and mental symptoms that can drastically affect quality of life (QoL). This study characterizes QoL in patients with CS, describes their treatment experiences, and identifies patient subsets associated with decreased QoL or shared impressions of treatment. METHODS: A 136-question survey addressing QoL factors and treatment experiences was completed by adult patients with CS from the Cushing Support and Research Foundation. Patient demographics, tumor characteristics, and treatment information were collected. Bivariate analyses were conducted to determine if patients' symptoms or treatment experiences were significantly associated with demographics or other variables. RESULTS: A total of 178 patients, predominantly female (94%) with mean age 53 years, completed the survey. Anxiety and/or depression (n = 163, 94%), loss of physical strength (n = 164, 93%), loneliness (n = 156, 90%), fatigue from treatment (n = 142, 89%), memory loss (n = 153, 88%), insomnia (n = 144, 83%), and pain (n = 141, 83%) were symptoms most commonly experienced by respondents. Patients experiencing delay of diagnosis >10 years were more likely to have suicidal thoughts (p = 0.002). Younger patients were more likely to express concerns about hair loss (p = 0.007), loneliness (p = 0.025), pain (p = 0.004), or the impact of CS on their marriage (p = 0.039) or children (p = 0.024). CONCLUSION: This survey demonstrates CS impacts patients across many dimensions, emphasizing the need for holistic support. We identified patient subsets in which QoL may be improved with additional patient resources or provider attention.

The SIEA SHRIMP Flap: An Ultrathin Axial Pattern Free Flap Useable in Obese Patients.

The reconstruction of distal extremity wounds poses a unique surgical challenge. In free tissue transfer, a thin, pliable skin flap is the ideal. Obese patients have a paucity of thin skin donor sites. Herein we report the discovery of a free SHRIMP flap (Superthin Harvest of a Reliable Islanded Medial Pannus flap) based on the SIEA vessels, harvested from a thick abdominal pannus at the time of cosmetic abdominoplasty. A 61-year-old woman with a chronic wound of the right Achilles tendon was evaluated for reconstruction after failing conservative measures. At the time of consultation, the patient expressed interest in abdominoplasty. Therefore, a skin flap from the abdomen or rectus abdominis muscle flap in the context of an abdominoplasty was offered. Despite obesity affecting the pannus, the superficial inferior epigastric vessels were found to course superficially beneath the dermis at time of abdominoplasty. This allowed straightforward harvest of a superthin flap of skin and minimal subcutaneous fat, which contoured to the ankle with an aesthetically pleasing outcome. The patient was satisfied with the results of her abdominoplasty and coverage of her chronic wound. The SHRIMP flap provides a straightforward, axial pattern, superthin free skin flap based on the superficial inferior epigastric vessels, and represents a useful option in obese patients. The flap can be combined with abdominoplasty for an aesthetic donor site.

Enhancing progestin therapy via HDAC inhibitors in endometrial cancer.

Uterine endometrial cancer (EC) incidence and deaths are on the rise. Hormone therapy, a traditional treatment regimen for this disease, uses progesterone and its synthetic analogue, progestin, to induce cell differentiation, apoptosis, and inhibition of invasion. This therapy is highly effective for progesterone receptor (PR) positive tumors in the short term. However, responsiveness decreases over time due to loss of PR expression; acquired resistance leads to treatment failure and poor prognosis. Primary resistance occurs in advanced, PR-negative tumors. Regardless, progestin therapy can be effective if the PR downregulation mechanism is reversed and if functional PR expression is restored. Using histone deacetylase inhibitors (HDACi), we inhibited cell proliferation in three EC cell lines and restored functional PR expression at the mRNA and protein levels. Two HDACi were tested using an endometrial xenograft tumor model: entinostat, an oral drug, and romidepsin, an IV drug. In vitro and in vivo studies support that entinostat decreased EC tumor growth, induced differentiation, and increased expression of the PR-targeted gene, PAEP. These findings supported the approval of a new NIH NCTN clinical trial, NRG-GY011, which concluded that dual treatment of MPA and entinostat, decreased expression of the proliferation marker, Ki67, but did not increase PR expression relative to single treatment with MPA in this short-term study. Therefore, a more potent HDACi, romidepsin, was investigated. Romidepsin treatment inhibited tumor growth and enhanced progestin treatment efficacy. More importantly, PR, PAEP, and KIAA1324 expressions were upregulated. Using a chromatin immunoprecipitation assay, we verified that HDACi can reverse PR downregulation mechanisms in mice models. Other potential drug efficacy markers, such as CD52, DLK1, GALNT9, and GNG2, were identified by transcriptome analysis and verified by q-PCR. Many of the upregulated drug efficacy markers predict favorable patient outcomes, while downregulated genes predict worse survival. Here, our current data suggests that romidepsin is a more potent HDACi that has the potential to achieve more robust upregulation of PR expression and may be a more promising candidate for future clinical trials.

Minimizing cotton ball retention in neurological procedures.

Neurosurgical operations are long and intensive medical procedures, during which the surgeon must constantly have an unobscured view of the brain in order to be able to properly operate, and thus must use a variety of tools to clear obstructions (like blood and fluid) from the operating area. Currently, cotton balls are the most versatile and effective option to accomplish this as they absorb fluids, are soft enough to safely manipulate the brain, act as a barrier between other tools and the brain, and function as a spacer to keep anatomies of the brain open and visible during the operation. While cotton balls allow neurosurgeons to effectively improve visibility of the operating area, they may also be accidentally left in the brain upon completion of the surgery. This can lead to a wide range of post-operative risks including dangerous immune responses, additional medical care or surgical operations, and even death. This project seeks to develop a unique medical device that utilizes ultrasound technology in order to minimize cotton retention after neurosurgical procedures in order to reduce undesired post-operative risks, and maximize visibility.