Greater Socioeconomic Deprivation is Associated with Increased Complication Rates and Lower Patient-Reported Outcomes Following Open Reduction and Internal Fixation of Humeral Shaft Fractures.

OBJECTIVES: This study explored the hypothesis that social determinants of health (SDOH), including racial and economic differences, may impact orthopaedic trauma outcomes in patients undergoing open reduction and internal fixation (ORIF) of humeral shaft fractures. METHODS: Design: Retrospective. SETTING: Single, academic, tertiary Level-I trauma center. PATIENT SELECTION CRITERIA: Adults with midshaft humerus fractures (AO/OTA 12) treated operatively with plate fixation from 05/2011 to 05/2021 with a minimum follow-up of nine months. OUTCOME MEASURES AND COMPARISONS: Radiographic fracture healing, complication rates, and patient-reported outcomes were investigated. SDOH were assessed using the Area Deprivation Index (ADI). Demographics, complications rates, and patient-reported clinical outcomes were compared between the first and fourth ADI quartiles. RESULTS: 196 patients fit the study criteria. The average age of the cohort was 47 years with 50 women (51%). Comparisons of the least deprived quartile (n=49) to the most deprived quartile (n=49) yielded similar sex distribution (59% vs 43% female, p=0.15), fewer non-white patients (8% vs 51%, p<0.01), older average age (51 years vs 43 years, p=0.05), similar BMI (30.5 vs. 31.8, p=0.45), and higher Charlson Comorbidity Index (CCI) (2.2 vs.1.1, p=0.03). While nonunion rates were similar (p=0.20) between groups, the most deprived quartile had 2.3 times greater odds of post-operative complications (p=0.04). Patients in the most deprived group exhibited higher PROMIS Pain Interference (PI) scores (p<0.01) and PROMIS Depression (D) scores (p=0.01), with lower PROMIS Physical Function (PF) scores (p<0.01) at 6-month follow-up than the least depriver cohort. The most deprived cohort had three times higher odds of missing scheduled appointments within the first post-operative year (p<0.01), resulting in a significantly higher no-show rate (p<0.01) than the least deprived cohort. Regression analysis including several demographic and injury factors identified that ADI was significantly associated with the occurrence of any missed appointments (p<0.01), no-show rates (p=0.04), and experiencing one of the following post-operative complications during recovery: Nonunion, radial nerve injury, or dysfunction (p=0.03). CONCLUSIONS: Patients experiencing greater resource deprivation faced increased odds of complications, missed appointments, and poorer PROMIS outcomes following humeral shaft fracture fixation, emphasizing that baseline socioeconomic disparities predict unfavorable post-operative outcomes even given favorable baseline health status according to the CCI score. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.

Quality control and validation of extracellular vesicles isolated from cultured human breast cancer cells.

OBJECTIVE: Extracellular vesicles (EVs) have been shown to play a critical role in promoting tumorigenesis. As EV research grows, it is of importance to have standardization of isolation, quality control, characterization and validation methods across studies along with reliable references to explore troubleshooting solutions. Therefore, our objective with this Research Note was to isolate EVs from multiple breast cancer cell lines and to describe and perform protocols for validation as outlined by the list of minimal information for studies of EVs (MISEV) from the International Society for Extracellular Vesicles. RESULTS: To isolate EVs, two techniques were employed: ultracentrifugation and size exclusion chromatography. Ultracentrifugation yielded better recovery of EVs in our hands and was therefore used for further validation. In order to satisfy the MISEV requirements, protein quantification, immunoblotting of positive (CD9, CD63, TSG101) and negative (TGFß1, ß-tubulin) markers, nanoflow cytometry and electron microscopy was performed. With these experiments, we demonstrate that yield of validated EVs varied between different breast cancer cell lines. Protocols were optimized to accommodate for low levels of EVs, and various technical and troubleshooting suggestions are included for potential application to other cell types that may provide benefit to investigators interested in future EV studies.

Providing the Tools to Facilitate Quality Care for Children with Sickle Cell Disease.

Meeting best-practice guidelines can significantly enhance quality of life and longevity for those with sickle cell disease (SCD). However, many clinical settings lack the necessary resources for optimal care. We present an integrated suite of tools and collaborative actions designed to enhance SCD care.

Lung-derived soluble factors support stemness/plasticity and metastatic behaviour of breast cancer cells via the FGF2-DACH1 axis.

Patients with triple-negative breast cancer (TNBC) have an increased propensity to develop lung metastasis. Our previous studies demonstrated that stem-like ALDHhiCD44+ breast cancer cells interact with lung-derived soluble factors, resulting in enhanced migration and lung metastasis particularly in TNBC models. We have also observed that the presence of a primary TNBC tumor can 'prime' the lung microenvironment in preparation for metastasis. In this study, we hypothesized that soluble lung-derived factors secreted in the presence of a primary TNBC tumor can influence stemness/plasticity of breast cancer cells. Using an ex vivo pulmonary metastasis assay (PuMA), we observed that the lung microenvironment supports colonization and growth of ALDHhiCD44+ TNBC cells, potentially via interactions with lung-derived FGF2. Exposure of TNBC cells to lung-conditioned media (LCM) generated from mice bearing TNBC primary tumors (tbLCM) significantly enhanced the proportion of ALDHhiCD44+ cells compared to control or LCM from tumor-naïve mice (tnLCM). Further analysis using a human cancer stem cell qPCR array revealed that, relative to tnLCM or control, exposure of TNBC cells to tbLCM leads to downregulation of the transcription factor and putative tumor suppressor Dachshund homolog 1 (DACH1), a downstream regulator of FGF2. In addition, inhibition of DACH1 using siRNA or treatment with recombinant FGF2 enhanced the ALDHhiCD44+ phenotype. Taken together, our findings suggest that the FGF2-DACH1 signaling axis supports stemness/plasticity of TNBC cells in the lung microenvironment and lays the foundation for future evaluation of FGF2 as a potential novel therapeutic target for treatment or prevention of breast cancer metastasis to the lung.

No Differences in Clinical, Functional, or Patient-Reported Outcomes Following Trial of Nonoperative Management Before Open Reduction and Internal Fixation of Humeral Shaft Fractures.

OBJECTIVES: To test the hypothesis that primary osteosynthesis of humeral shaft fractures may lead to more favorable clinical, functional, and patient-reported outcomes than fixation following a trial of nonoperative management. DESIGN: Retrospective cohort review. SETTING: Academic level I trauma center. PATIENT SELECTION CRITERIA: Adult patients who presented with humeral shaft fractures and ultimately underwent open reduction and internal fixation (ORIF) from May 2011 to May 2021. Patients who underwent ORIF within 2 weeks of injury were grouped into the primary osteosynthesis cohort, and patients who underwent ORIF >4 weeks from the date of injury were grouped into the trial of nonoperative cohort. OUTCOME MEASURES AND COMPARISONS: Postoperative complications, elbow arc of motion, time to radiographic union, and patient-reported outcomes were investigated and compared between the primary osteosynthesis and trial of nonoperative management cohorts. RESULTS: One hundred twenty-seven patients fit the study criteria, 84 underwent primary osteosynthesis and 43 trialed initial nonoperative treatment. No differences were found in patient demographics between the primary osteosynthesis and trial of nonoperative management cohorts, including age (53 ± 19 vs. 57 ± 18; P = 0.25), sex (39% vs. 44% male, 61% vs. 56% female; P = 0.70), and Body Mass Index (BMI) (30 ± 6 vs. 32 ± 9; P = 0.38). The average time to operative intervention in the primary osteosynthesis group was 4 days (0-14 days) and 105 days (28-332 days) in the trial of nonoperative treatment group ( P < 0.01). No differences were found with regard to intraoperative blood loss, total operative time, time to radiographic union (determined using the Radiographic Union Scores for Humeral scoring system), or overall complication rates, including primary and secondary radial nerve injuries ( P = 0.23 and 0.86, respectively). Patients reported similar patient-reported outcomes measurement information system pain interference ( P = 0.73), depression (D) ( P = 0.99), and physical function ( P = 0.66) scores at their 6-month postsurgical follow-up visits. CONCLUSIONS: Patients who attempted a trial of nonoperative management for humeral shaft fractures before ORIF had similar clinical, functional, and patient-reported outcomes as those who underwent primary osteosynthesis. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Adjunctive dorsal spanning plate fixation for challenging distal radius injuries.

Background: Distal radius fractures with severely osteoporotic bone or articular comminution can provide challenges to fixation with traditional volar locked plating alone. The purpose of this study was to evaluate the clinical, radiographic, and patient reported outcomes of patients undergoing distal radius fixation with volar locked plating and adjunctive dorsal bridge plating. Methods: We retrospectively identified 16 patients with distal radius fractures who underwent our preferred surgical technique for fixation. Patients underwent volar locked plate fixation as well as dorsal bridge fixation at time of surgery. Seven patients were indicated for severe articular comminution with volar rim fragmentation (44%), three patients were revised for nonunion after previous volar locked late fixation (19%), and six patients had severely osteoporotic bone with articular comminution (38%). Two patients (13%) sustained AO/OTA 23-A3 distal radius fracture, two patients (13%) had a 23-B3 fracture, two patients (13%) had a 23-C2 fracture and ten patients (63%) had a 23-C3 fracture. Results: The average patient age was 51.8 years ± 20.6. Patients were followed for an average of 12.2±6.3 months. The dorsal bridge plate was removed at an average of 11.1±2.4 weeks. The average post-operative radial inclination was 18.9±2.4°, radial height 12.4 mm ± 2.6 mm, and volar tilt 7.1±1.9°. There were no cases of deep or superficial infection. After dorsal bridge plate removal, patients demonstrated an average wrist extension of 55.3±9.5°, flexion 54.4±12.8°, radial deviation 15.7±3.2°, 25.2±3.9 degrees of ulnar deviation. Conclusion: Distal radius fractures in the setting of severely osteoporotic bone, salvage procedures, articular comminution, volar rim fractures, and revision surgery present uniquely difficult surgical challenges. Volar locked plating with adjunctive dorsal bridge plating can be used with good short- and long-term results.

PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy.

An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma.

Comparable Injury to the Indirect Head of the Rectus Femoris During Interportal and Periportal Capsulotomy: A Cadaveric Study.

Background: There is concern for maintaining the integrity of the reflected head of the rectus femoris during arthroscopic hip joint access. Because of the proximity to the indirect head of the rectus femoris (IHRF), capsulotomy technique and capsular closure during routine hip arthroscopy may play a role in postoperative tendinitis. Purpose: To quantify the extent of injury sustained to the IHRF during interportal versus periportal capsulotomy for routine arthroscopic hip joint access. Study Design: Controlled laboratory study. Methods: A cadaveric study was conducted using 20 fresh-frozen cadaveric hips, in which hip joint access through a periportal capsulotomy (n = 10) or interportal capsulotomy (n = 10) was performed. Capsular closure followed by a layered dissection to the capsuloligamentous complex of the hip joint was then performed to localize the IHRF. Suture proximity to the tendon, tendon disruption, and the IHRF footprint was documented to the nearest 0.01 mm using digital calipers. Statistical analysis was performed using unpaired Student t tests. Results: The mean capsulotomy length for the interportal specimens was 19.27 ± 3.25 mm, and the mean medial and lateral capsulotomy length for the periportal specimens was 4.47 ± 1.60 and 4.26 ± 0.89 mm, respectively. There was violation of the tendon in 3 of 10 interportal specimens and 4 of 10 periportal specimens. There was no significant difference in the closest suture measured to the IHRF for specimens with versus without tendon violation, for either interportal or periportal capsulotomy. Conclusion: We found comparable outcomes with regard to violation of the IHRF between interportal and periportal capsulotomy, with no significant difference in suture proximity to the IHRF in specimens with or without tendon violation. There remains no consensus on the ideal method by which to avoid iatrogenic damage to the IHRF. Clinical Relevance: Our findings provide insight that may lead to future advances in surgical care, such that protection of the tendon during routine hip arthroscopy may allow for improved postoperative rehabilitation and strength.

Altered binding affinity of SIX1-Q177R correlates with enhanced WNT5A and WNT pathway effector expression in Wilms tumor.

Wilms tumors present as an amalgam of varying proportions of tissues located within the developing kidney, one being the nephrogenic blastema comprising multipotent nephron progenitor cells (NPCs). The recurring missense mutation Q177R in NPC transcription factors SIX1 and SIX2 is most correlated with tumors of blastemal histology and is significantly associated with relapse. Yet, the transcriptional regulatory consequences of SIX1/2-Q177R that might promote tumor progression and recurrence have not been investigated extensively. Utilizing multiple Wilms tumor transcriptomic datasets, we identified upregulation of the gene encoding non-canonical WNT ligand WNT5A in addition to other WNT pathway effectors in SIX1/2-Q177R mutant tumors. SIX1 ChIP-seq datasets from Wilms tumors revealed shared binding sites for SIX1/SIX1-Q177R within a promoter of WNT5A and at putative distal cis-regulatory elements (CREs). We demonstrate colocalization of SIX1 and WNT5A in Wilms tumor tissue and utilize in vitro assays that support SIX1 and SIX1-Q177R activation of expression from the WNT5A CREs, as well as enhanced binding affinity within the WNT5A promoter that may promote the differential expression of WNT5A and other WNT pathway effectors associated with SIX1-Q177R tumors.

Assessment of Fungal Succession in Decomposing Swine Carcasses (Sus scrofa L.) Using DNA Metabarcoding.

The decomposition of animal bodies is a process defined by specific stages, described by the state of the body and participation of certain guilds of invertebrates and microorganisms. While the participation of invertebrates in decomposing is well-studied and actively used in crime scene investigations, information on bacteria and fungi from the scene is rarely collected or used in the identification of important factors such as estimated time of death. Modern molecular techniques such as DNA metabarcoding allow the identification and quantification of the composition of microbial communities. In this study, we used DNA metabarcoding to monitor fungal succession during the decomposition of juvenile pigs in grasslands of New Jersey, USA. Our findings show that decomposition stages differ in a diversity of fungal communities. In particular, we noted increased fungal species richness in the more advanced stages of decomposition (e.g., bloat and decay stages), with unique fungal taxa becoming active with the progression of decay. Overall, our findings improve knowledge of how fungi contribute to forensically relevant decomposition and could help with the assessment of crime scenes.

Increased Neighborhood Deprivation Is Associated with Prolonged Hospital Stays After Surgical Fixation of Traumatic Pelvic Ring Injuries.

BACKGROUND: The purpose of this study was to understand the role of social determinants of health assessed by the Area Deprivation Index (ADI) on hospital length of stay and discharge destination following surgical fixation of pelvic ring fractures. METHODS: A retrospective chart analysis was performed for all patients who presented to our level-I trauma center with pelvic ring injuries that were treated with surgical fixation. Social determinants of health were determined via use of the ADI, a comprehensive metric of socioeconomic status, education, income, employment, and housing quality. ADI values range from 0 to 100 and are normalized to a U.S. mean of 50, with higher scores representing greater social deprivation. We stratified our cohort into 4 ADI quartiles. Statistical analysis was performed on the bottom (25th percentile and below, least deprived) and top (75th percentile and above, most deprived) ADI quartiles. Significance was set at p < 0.05. RESULTS: There were 134 patients who met the inclusion criteria. Patients in the most deprived group were significantly more likely to have a history of smoking, to self-identify as Black, and to have a lower mean household income (p = 0.001). The most deprived ADI quartile had a significantly longer mean length of stay (and standard deviation) (19.2 ± 19 days) compared with the least deprived ADI quartile (14.7 ± 11 days) (p = 0.04). The least deprived quartile had a significantly higher percentage of patients who were discharged to a resource-intensive skilled nursing facility or inpatient rehabilitation facility compared with those in the most deprived quartile (p = 0.04). Race, insurance, and income were not significant predictors of discharge destination or hospital length of stay. CONCLUSIONS: Patients facing greater social determinants of health had longer hospital stays and were less likely to be discharged to resource-intensive facilities when compared with patients of lesser social deprivation. This may be due to socioeconomic barriers that limit access to such facilities. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy.

An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti-cancer immune responses and offers a new avenue for treating various types of cancer.

Influence of Extracellular Vesicles on Lung Stromal Cells during Breast Cancer Metastasis.

Breast cancer is a prominent cause of cancer diagnosis and death in women globally, with over 90% of deaths being attributed to complications that arise from metastasis. One of the common locations for breast cancer metastasis is the lung, which is associated with significant morbidity and mortality. Curative treatments for metastatic breast cancer patients are not available and the molecular mechanisms that underlie lung metastasis are not fully understood. In order to better treat these patients, identifying events that occur both prior to and during metastatic spread to the lung is essential. Several studies have demonstrated that breast cancer-derived extracellular vesicles secreted from the primary breast tumor play a key role in establishing the lung pre-metastatic niche to support colonization of metastatic tumor cells. In this review, we summarize recent work supporting the influence of extracellular vesicles on stromal components of the lung to construct the pre-metastatic niche and support metastasis. Furthermore, we discuss the potential clinical applications of utilizing extracellular vesicles for diagnosis and treatment. Together, this review highlights the dynamic nature of extracellular vesicles, their roles in breast cancer metastasis to the lung, and their value as potential biomarkers and therapeutics for cancer prevention.

MycoPins: a metabarcoding-based method to monitor fungal colonization of fine woody debris.

The MycoPins method described here is a rapid and affordable protocol to monitor early colonization events in communities of wood-inhabiting fungi in fine woody debris. It includes easy to implement field sampling techniques and sample processing, followed by data processing, and analysis of the development of early dead wood fungal communities. The method is based on fieldwork from a time series experiment on standard sterilized colonization targets followed by the metabarcoding analysis and automated molecular identification of species. This new monitoring method through its simplicity, moderate costs, and scalability paves a way for a broader and scalable project pipeline. MycoPins establishes a standard routine for research stations or regularly visited field sites for monitoring of fungal colonization of woody substrates. The routine uses widely available consumables and therefore presents a unifying method for monitoring of fungi of this type.

A Systematic Review of Periprocedural Risk Prediction Scores in Chronic Total Occlusion Percutaneous Coronary Intervention.

Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is associated with high incidence of complications. We queried PubMed and the Cochrane Library (last search: October 26, 2022) for CTO PCI-specific periprocedural complication risk scores. We identified 8 CTO PCI-specific risk scores: (1) Angiographic coronary artery perforation (OPEN-CLEAN [Outcomes, Patient Health Status, and Efficiency iN (OPEN) Chronic Total Occlusion (CTO) Hybrid Procedures - CABG, Length (occlusion), EF <50%, Age, CalcificatioN] perforation, c-statistic 0.75): previous coronary artery bypass graft surgery, occlusion length 20 to 60 mm or ≥60 mm, left ventricular ejection fraction (LVEF) <50%, age 50 to 70 years or ≥70 years, heavy calcification. (2) Major adverse cardiovascular events (MACE) (PROGRESS-CTO complication, c-statistic 0.76): age >65 years, lesion length ≥23 mm, retrograde strategy, and (3) MACE (PROGRESS-CTO MACE, c-statistic 0.74): age ≥65 years, female gender, moderate/severe calcification, blunt/no stump, anterograde dissection and re-entry (ADR) or retrograde strategy. (4) All-cause mortality (PROGRESS-CTO mortality, c-statistic 0.80): age ≥65, moderate/severe calcification, LVEF ≤45%, ADR or retrograde strategy. (5) Perforation requiring pericardiocentesis (PROGRESS-CTO pericardiocentesis, c-statistic 0.78): age ≥65 years, moderate/severe calcification, female gender, ADR or retrograde strategy. (6) Acute myocardial infarction (PROGRESS-CTO acute myocardial infarction, c-statistic 0.72): previous coronary artery bypass graft surgery, atrial fibrillation, blunt/no stump. (7) Perforation requiring any treatment (PROGRESS-CTO perforation, c-statistic 0.74): age ≥65 years, moderate/severe calcification, blunt/no stump, ADR, or retrograde strategy. (8) Contrast-induced acute kidney injury (c-statistic 0.84): age ≥75, LVEF <40%, serum creatinine >1.5 mg/100 ml, serum albumin ≤30, 3040 g/L. There are 8 CTO PCI periprocedural risk scores that may facilitate risk assessment and procedural planning in patients who underwent CTO PCI.

Editorial Commentary: Social Determinants of Health Influence the Success of Shoulder Rotator Cuff Repair Outcomes: When You Do Everything Right, Yet Things Still Go Wrong.

Our ability to perform a technically sound surgery is not sufficient to ensure patients have an excellent clinical outcome. Social determinants of health disparities (SDHDs) profoundly impact health equality. Health disparities that exist in the United States are risk factors for inferior patient-reported outcomes and result in greater complication rates following rotator cuff repair surgery. The presence of SDHDs was associated with an increased risk of revision, stiffness, emergency department visits, medical complications, and costs. Economic and educational SDHDs were associated with the greatest risk of 1-year revision surgery. Improved understanding of these social variables can help with risk identification preoperatively. Surgeons may employ additional, holistic, bio-psycho-social, perioperative resources to provide high-quality, value-based care to at-risk patients who might be marginalized by our health care system.

α-Synuclein modulates fibronectin expression in the trabecular meshwork independent of TGFß2.

α-Synuclein (α-Syn) is implicated in Parkinson's disease (PD), a neuromotor disorder with prominent visual symptoms. The underlying cause of motor dysfunction has been studied extensively, and is attributed to the death of dopaminergic neurons mediated in part by intracellular aggregation of α-Syn. The cause of visual symptoms, however, is less clear. Neuroretinal degeneration due to the presence of aggregated α-Syn has been reported, but the evidence is controversial. Other symptoms including those arising from primary open angle glaucoma (POAG) are believed to be the side-effects of medications prescribed for PD. Here, we explored the alternative hypothesis that dysfunction of α-Syn in the anterior eye alters the interaction between the actin cytoskeleton of trabecular meshwork (TM) cells with the extracellular matrix (ECM), impairing their ability to respond to physiological changes in intraocular pressure (IOP). A similar dysfunction in neurons is responsible for impaired neuritogenesis, a characteristic feature of PD. Using cadaveric human and bovine TM tissue and primary human TM cells as models, we report two main observations: 1) α-Syn is expressed in human and bovine TM cells, and significant amounts of monomeric and oligomeric α-Syn are present in the AH, and 2) primary human TM cells and human and bovine TM tissue endocytose extracellular recombinant monomeric and oligomeric α-Syn via the prion protein (PrPC), and upregulate fibronectin (FN) and α-smooth muscle actin (α-SMA), fibrogenic proteins implicated in POAG. Transforming growth factor ß2 (TGFß2), a fibrogenic cytokine implicated in ∼50% cases of POAG, is also increased, and so is RhoA-associated coiled-coil-containing protein kinase 1 (ROCK-1). However, silencing of α-Syn in primary human TM cells reduces FN, α-SMA, and ROCK-1 in the absence or presence of over-expressed active TGFß2, suggesting modulation of FN and ROCK-1 independent of, or upstream of TGFß2. These observations suggest that extracellular α-Syn modulates ECM proteins in the TM independently or via PrPC by activating the RhoA-ROCK pathway. These observations reveal a novel function of α-Syn in the anterior eye, and offer new therapeutic options.

CAR T cell therapy in solid tumors: A review of current clinical trials.

Chimeric antigen receptor (CAR) T cell therapy has made tremendous strides in the arena of hematological malignancies with approved therapies in certain leukemias, lymphomas, and recently myeloma with overall highly favorable response rates. While numerous clinical studies are still ongoing for hematological malignancies, research is developing to translate the feasibility of CAR T therapy in solid organ malignancies. Unfortunately, the majority of diagnosed cancers are primarily solid tumors. Thus, a highly unmet clinical need for further research and development exists in this field. This review article highlights currently active clinical trials and a few pertinent preclinical studies involving CAR T cell therapy in solid tumors while briefly discussing study outcomes and potential key targets that may allow for the feasibility of this therapy option. Finally, we mention critical challenges existing in the solid tumor environment and discuss developing strategies that may potentially overcome the existing barriers to CAR T cell progress in solid tumors.

The Lean Six Sigma Define, Measure, Analyze, Implement, Control (LSS DMAIC) Framework: An Innovative Strategy for Quality Improvement of Pharmacist Vaccine Recommendations in Community Pharmacy.

Community pharmacies represent a highly accessible and convenient setting for vaccination. However, setting-specific barriers exist which contribute to suboptimal vaccination rates, particularly for pneumococcal vaccinations. One proven quality improvement framework growing in use within healthcare settings is Lean Six Sigma (LSS). This paper describes the application of the LSS framework in select locations of a national pharmacy chain. The implementation of a training program for improved recommendation techniques to promote higher rates of pneumococcal vaccinations in high-risk adult populations is also addressed. A mixed-methods approach including pre/post quasi-experimental design and in-depth key informant interviews was used.