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Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of G i1 -bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of G i1 -bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.

Alzheimer’s disease (AD) is a major cause of age-related dementia and is characterized by progressive brain damage that gradually destroys memory and the ability to learn, which ultimately leads to the decline of a patient’s ability to perform daily activities. Although some of the pharmacological treatments of AD are available for symptomatic relief, they are not able to limit the progression of AD and have several side effects. Mesenchymal stem/stromal cells (MSCs) could be a potential therapeutic option for treating AD due to their immunomodulatory, anti-inflammatory, regenerative, antioxidant, anti-apoptotic, and neuroprotective effects. MSCs not only secret neuroprotective and anti-inflammatory factors to promote the survival of neurons, but they also transfer functional mitochondria and miRNAs to boost their bioenergetic profile as well as improve microglial clearance of accumulated protein aggregates. This review focuses on different clinical and preclinical studies using MSC as a therapy for treating AD, their outcomes, limitations and the strategies to potentiate their clinical translation.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.

Prostate cancer remains the most common non-cutaneous malignancy among men in the United States. To discover potential serum-based biomarkers for high-risk prostate cancer, we performed a high-multiplex immunoassay utilizing patient-matched pre-operative and post-operative serum samples from ten men with high-grade and high-volume prostate cancer. Our study identified six (CASP8, MSLN, FGFBP1, ICOSLG, TIE2 and S100A4) out of 174 proteins that were significantly decreased after radical prostatectomy. High levels of CASP8 were detected in pre-operative serum samples when compared to post-operative serum samples and serum samples from patients with benign prostate hyperplasia (BPH). By immunohistochemistry, CASP8 protein was expressed at higher levels in prostate cancer tissues compared to non-cancerous and BPH tissues. Likewise, CASP8 mRNA expression was significantly upregulated in prostate cancer when compared to benign prostate tissues in four independent clinical datasets. In addition, mRNA levels of CASP8 were higher in patients with recurrent prostate cancer when compared to patients with non-recurrent prostate cancer and high expression of CASP8 was associated with worse disease-free survival and overall survival in renal cancer. Together, our results suggest that CASP8 may potentially serve as a biomarker for high-risk prostate cancer and possibly renal cancer.

Distinguishing indolent from clinically significant localized prostate cancer is a major clinical challenge and influences clinical decision-making between treatment and active surveillance. The development of novel predictive biomarkers will help with risk stratification, and clinical decision-making, leading to a decrease in over or under-treatment of patients with prostate cancer. Here, we report that Trop2 is a prognostic tissue biomarker for clinically significant prostate cancer by utilizing the Canary Prostate Cancer Tissue Microarray (CPCTA) cohort composed of over 1100 patients from a multi-institutional study. We demonstrate that elevated Trop2 expression is correlated with worse clinical features including Gleason score, age, and pre-operative PSA levels. More importantly, we demonstrate that elevated Trop2 expression at radical prostatectomy predicts worse overall survival in men undergoing radical prostatectomy. Additionally, we detect shed Trop2 in urine from men with clinically significant prostate cancer. Our study identifies Trop2 as a novel tissue prognostic biomarker and a candidate non-invasive marker for prostate cancer.

Breast cancer remains the second most lethal cancer among women in the United States and triple-negative breast cancer is the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. In this study, we demonstrate that Trop2 is overexpressed in triple-negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC cell and tumor growth supporting the oncogenic role of Trop2 in breast cancer. Through proteomic profiling, we discovered a metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK proteins that were downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-mediated metabolic gene signature is significantly upregulated in TNBC patients across multiple RNA-expression clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stages of the disease. Taken together, our study identified a new five-gene metabolic signature as an accurate predictor of breast cancer outcome.

Background Postoperative sepsis is associated with high mortality and the national costs of septicemia exceed those of any other diagnosis. While numerous studies in the basic orthopedic science literature suggest that traumatic injuries facilitate the development of sepsis, it is currently unclear whether orthopedic trauma patients are at increased risk. The purpose of this study was thus to assess the incidence of sepsis and determine the risk factors that significantly predicted septicemia following orthopedic trauma surgery. Materials and methods 56,336 orthopedic trauma patients treated between 2006 and 2013 were identified in the ACS-NSQIP database. Documentation of postoperative sepsis/septic shock, demographics, surgical variables, and preoperative comorbidities was collected. Chi-squared analyses were used to assess differences in the rates of sepsis between trauma and nontrauma groups. Binary multivariable regressions identified risk factors that significantly predicted the development of postoperative septicemia in orthopedic trauma patients. Results There was a significant difference in the overall rates of both sepsis and septic shock between orthopedic trauma (1.6%) and nontrauma (0.5%) patients ( p  < 0.001). For orthopedic trauma patients, ventilator use (OR = 15.1, p  = 0.002), history of pain at rest (OR = 2.8, p  = 0.036), and prior sepsis (OR = 2.6, p  < 0.001) were significantly associated with septicemia. Statistically predictive, modifiable comorbidities included hypertension (OR = 2.1, p  = 0.003) and the use of corticosteroids (OR = 2.1, p  = 0.016). Conclusions There is a significantly greater incidence of postoperative sepsis in the trauma cohort. Clinicians should be aware of these predictive characteristics, may seek to counsel at-risk patients, and should consider addressing modifiable risk factors such as hypertension and corticosteroid use preoperatively. Level of evidence Level III.

Background Ankle fracture is one of the most common injuries treated by orthopaedic surgeons, and its incidence is only expected to rise with an aging population. It is also associated with often costly complications, yet there is little literature on risk factors, especially modifiable ones, driving these complications. The aim of this study is to reveal whether inpatient treatment after ankle fracture is associated with higher incidence of postoperative complications. As the USA moves towards a bundled payment healthcare system, it is imperative that orthopaedists maximize patient outcome and quality of care while also reducing overall costs. Materials and methods We used the American College of Surgeons National Surgical Quality Improvement Program database to compare complication rates between inpatient and outpatient treatment of ankle fracture. We collected patient demographics, comorbidities, and postoperative complications from both groups, then compared treatments using a multinomial logistic regression model. Results We identified 7383 patients, with 2630 (36%) in the outpatient and 2630 (36%) in the inpatient group. Of these, 104 (4.0%) inpatients compared with 52 (2.0%) outpatients developed a complication ( p  < 0.001). Conclusions Inpatients developed major complications including deep wound infection and pulmonary embolism, as well as minor complications such as pneumonia and urinary tract infection, at significantly greater rates. As reimbursement models begin to incorporate value-based care, orthopaedic surgeons need to be aware of factors associated with increased incidence of postoperative complications. Level of evidence Level III retrospective comparative study.

Background The role and outcome of radical surgery in contemporary multidisciplinary management of breast cancer patients presenting with isolated sternal or full-thickness chest wall (SCW) recurrence are undefined compared with patients treated without surgery. Methods Detailed analyses of all patients with isolated SCW recurrence treated from 1992 to 2011 at a large cancer institution were performed. Univariate and multivariate comparisons of clinicopathologic and treatment characteristics were analyzed. Overall and progression-free survival were compared using the Kaplan–Meier method. Results Seventy-six patients were identified, 44 treated surgically and 32 nonsurgically. Overall survival at 5 years was not statistically different between patients who underwent surgery and those who did not (30.6 and 49.6 %, respectively; P  = 0.52) although patients selected for surgery presented with more advanced and biologically aggressive disease. Surgically treated patients were more likely to have triple-negative breast cancer at recurrence (52 vs. 17 %; P  = 0.006). Among surgical patients, 95 % received preoperative systemic therapy. Clinical response with systemic therapy was significantly different, with surgically treated patients more likely to have responsive or stable disease (54 vs. 25 %, P  = 0.04). Complications related to radical surgical resection occurred in 25 % of patients. For hormone receptor–positive recurrence, 5-year progression-free survival was significantly higher among surgical patients (46.3 vs. 14.5 %; P  = 0.01). Conclusions Among patients with isolated SCW recurrence, hormone receptor-positive recurrence is associated with improved survival. Systemic therapy should be the initial treatment, and clinical response can be used to help select patients who may benefit from radical resection.

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.