Exosome-delivered miR-221/222 exacerbates tumor liver metastasis by targeting SPINT1 in colorectal cancer

MicroRNAs (miRNAs) are involved in the progression of many cancers through largely unelucidated mechanisms. The results of our present study identified a gene cluster, miR-221/222, that is constitutively upregulated in serum exosome samples of patients with colorectal carcinoma (CRC) with liver metastasis (LM); this upregulation predicts a poor overall survival rate. Using an in vitro cell coculture model, we demonstrated that CRC exosomes harboring miR-221/222 activate liver hepatocyte growth factor (HGF) by suppressing SPINT1 expression. Importantly, miR-221/222 plays a key role in forming a favorable premetastatic niche (PMN) that leads to the aggressive nature of CRC, which was further shown through in vivo studies. Overall, our results show that exosomal miR-221/222 promotes CRC progression and may serve as a novel prognostic marker and therapeutic target for CRC with LM.     

iRGD‐modified exosomes effectively deliver CPT1A siRNA to colon cancer cells,reversing oxaliplatin resistance by regulating fatty acid oxidation

Fatty acid oxidation (FAO) plays a vital role in drug resistance in cancer cells. Carnitine palmitoyltransferase 1A (CPT1A), a key enzyme of FAO, is widely recognized as an emerging therapeutic target. Here, we confirmed that CPT1A was heterogeneously expressed in colon cancer cells, with a high expression in oxaliplatin‐resistant cells but low expression in oxaliplatin‐sensitive cells, and expression could be increased by oxaliplatin stimulation. In addition, we verified that CPT1A was more highly expressed in colon cancer tissues than in noncancerous tissues. Silencing CPT1A by siRNA or etomoxir, a specific small‐molecule inhibitor of CPT1A, could reverse the sensitivity of drug‐resistant colon cancer cells to oxaliplatin. Subsequently, the combination of oxaliplatin with CPT1A inhibition promoted apoptosis and inhibited proliferation. In addition, exosomes were generated with the iRGD peptide on the surface, which showed highly efficient targeting compared with control exosomes in vivo. Furthermore, we loaded and therapeutically applied iRGD‐modified exosomes with siCPT1A to specifically deliver siCPT1A into tumours to suppress FAO. As a consequence, iRGD‐modified exosomes showed the significant inhibition of CPT1A in tumour tissues and exhibited the ability to reverse oxaliplatin resistance and inhibit tumour growth by inhibiting FAO with high safety in vivo.     

Novel in vitro comparative model of osteogenic and inflammatory cell response to dental implants

Objectives

Roughened dental implants promote mesenchymal stem cell (MSCs) osteoblastic differentiation, and hydrophilic modifications induce anti-inflammatory macrophages activation. While the effect of different surface modifications on osseointegration of commercial dental implants have been compared in vivo and clinically, the initial cellular response to these modifications often overlooked. We aimed to characterize the macrophage inflammatory response and MSC osteogenesis across different commercially available implants in vitro.

Posttraumatic Stress Disorder and Barriers to Care in Eastern Cape Province,South Africa

A range of barriers to seeking mental health care in low‐ and middle‐income countries has been investigated. Little, however, is known of the barriers to care and help‐seeking behavior among people with posttraumatic stress disorder (PTSD) in low‐ and middle‐income countries. This was a population‐based study including 977 people aged 18–40 years from the Eastern Cape Province in South Africa. Current PTSD was assessed by using a diagnostic questionnaire (Mini International Psychiatric Interview). An additional questionnaire captured socioeconomic and health‐related data. The prevalence of current PTSD was 10.8%. Only 48.1% of people with current PTSD accessed health care services. Younger people aged 18 to 29 years were less likely to seek health care, OR = 0.36, 95% CI [0.15, 0.85]. People earning a salary or wage, OR = 2.91, 95% CI [1.26, 6.71]; and those with tuberculosis, OR = 11.63, 95% CI [1.42, 95.56], were more likely to seek health care. A range of barriers to seeking care were identified, the most striking being stigma and a lack of knowledge regarding the nature and treatment of mental illness. People with current PTSD may seek help for other health concerns and brief screening means those affected may be readily identified.     

Questioning the "big assumptions". Part II: recognizing organizational contradictions that impede institutional change

BACKGROUND: Well-designed medical curriculum reforms can fall short of their primary objectives during implementation when unanticipated or unaddressed organizational resistance surfaces. This typically occurs if the agents for change ignore faculty concerns during the planning stage or when the provision of essential institutional safeguards to support new behaviors are neglected. Disappointing outcomes in curriculum reforms then result in the perpetuation of or reversion to the status quo despite the loftiest of goals. Institutional resistance to change, much like that observed during personal development, does not necessarily indicate a communal lack of commitment to the organization's newly stated goals. It may reflect the existence of competing organizational objectives that must be addressed before substantive advances in a new direction can be accomplished. OBJECTIVE: The authors describe how the Big Assumptions process (see previous article) was adapted and applied at the institutional level during a school of medicine's curriculum reform. Reform leaders encouraged faculty participants to articulate their reservations about considered changes to provided insights into the organization's competing commitments. The line of discussion provided an opportunity for faculty to appreciate the gridlock that existed until appropriate test of the school's long held Big Assumptions could be conducted. CONCLUSIONS: The Big Assumptions process proved useful in moving faculty groups to recognize and questions the validity of unchallenged institutional beliefs that were likely to undermine efforts toward change. The process also allowed the organization to put essential institutional safeguards in place that ultimately insured that substantive reforms could be sustained.     

Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR-133/PRDM16 pathway

Cancer-related cachexia is a metabolic syndrome characterized by a wasting disorder of adipose and skeletal muscle and is accompanied by body weight loss and systemic inflammation. The treatment options for cancer cachexia are limited, and the molecular mechanism remains poorly understood. Circular RNAs (circRNAs) are a novel family of endogenous noncoding RNAs that have been proposed to regulate gene expression in mammals. Exosomes are small vesicles derived from cells, and recent studies have shown that circRNAs are stable in exosomes. However, little is known about the biological role of circRNAs in exosomes. In our study, we showed that circRNAs in plasma exosomes have specific expression features in gastric cancer (GC), and ciRS-133 is linked with the browning of white adipose tissue (WAT) in GC patients. Exosomes derived from GC cells deliver ciRS-133 into preadipocytes, promoting the differentiation of preadipocytes into brown-like cells by activating PRDM16 and suppressing miR-133. Moreover, knockdown of ciRS-133 reduced cancer cachexia in tumor-implanted mice, decreasing oxygen consumption and heat production. Thus, exosome-delivered circRNAs are involved in WAT browning and play a key role in cancer-associated cachexia.     

The Incremental Value of Right Ventricular Size and Strain in the Risk Assessment of Right Heart Failure Post - Left Ventricular Assist Device Implantation

Background

Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is associated with high morbidity and mortality. Existing risk scores include semiquantitative evaluation of right ventricular (RV) dysfunction. This study aimed to determine whether quantitative evaluation of both RV size and function improve risk stratification for RHF after LVAD implantation beyond validated scores.

Optimizing right ventricular focused four-chamber views using three-dimensional imaging,a comparative magnetic resonance based study

Obtaining focused right ventricular (RV) apical view remains challenging using conventional two-dimensional (2D) echocardiography. This study main objective was to determine whether measurements from RV focused views derived from three-dimensional (3D) echocardiography (3D-RV-focused) are closely related to measurements from magnetic resonance (CMR). A first cohort of 47 patients underwent 3D echocardiography and CMR imaging within 2 h of each other. A second cohort of 25 patients had repeat 3D echocardiography to determine the test–retest characteristics; and evaluate the bias associated with unfocused RV views. Tomographic views were extracted from the 3D dataset: RV focused views were obtained using the maximal RV diameter in the transverse plane, and unfocused views from a smaller transverse diameter enabling visualization of the tricuspid valve opening. Measures derived using the 3D-RV-focused view were strongly associated with CMR measurements. Among functional metrics, the strongest association was between RV fractional area change (RVFAC) and ejection fraction (RVEF) (r?=?0.92) while tricuspid annular plane systolic excursion moderately correlated with RVEF (r?=?0.47), all p?<?0.001. Among RV size measures, the strongest association was found between RV end-systolic area (RVESA) and volume (r?=?0.87, p?<?0.001). RV unfocused views led on average to 10% underestimation of RVESA. The 3D-RV-focused method had acceptable test–retest characteristics with a coefficient of variation of 10% for RVESA and 11% for RVFAC. Deriving standardized RV focused views using 3D echocardiography strongly relates to CMR-derived measures and may improve reproducibility in RV 2D measurements.