Water-Soluble Molecular Cages for Biological Applications.

The field of molecular cages has attracted increasing interest in relation to the development of biological applications, as evidenced by the remarkable examples published in recent years. Two key factors have contributed to this achievement: First, the remarkable and adjustable host-guest chemical properties of molecular cages make them highly suitable for biological applications. This allows encapsulating therapeutic molecules to improve their properties. Second, significant advances have been made in synthetic methods to create water-soluble molecular cages. Achieving the necessary water solubility is a significant challenge, which in most cases requires specific chemical groups to overcome the inherent hydrophobic nature of the molecular cages which feature the organic components of the cage. This can be achieved by either incorporating water-solubilizing groups with negative/positive charges, polyethylene glycol chains, etc.; or by introducing charges directly into the cage structure itself. These synthetic strategies allow preparing water-soluble molecular cages for diverse biological applications, including cages' anticancer activity, anticancer drug delivery, photodynamic therapy, and molecular recognition of biological molecules. In the review we describe selected examples that show the main concepts to achieve water solubility in molecular cages and some selected recent biological applications.

Complex Urethral Diverticulectomy: Is a Synchronous Prophylactic Autologous Fascial Sling Needed?

IMPORTANCE: Urethral diverticulectomy is performed with or without concomitant pubovaginal sling (PVS). Patients with complex UD are more frequently offered concomitant PVS. However, there is paucity of literature comparing postoperative incontinence rates for patients with simple versus complex UD. OBJECTIVE: The objective of this study is to examine postoperative stress urinary incontinence (SUI) rates after Urethral Diverticulectomy without concomitant PVS for both complex and simple cases. STUDY DESIGN: A retrospective cohort study was conducted among 55 patients who underwent Urethral Diverticulectomy from 2007 to 2021. Preoperative SUI was patient-reported and confirmed with cough stress test result. Complex cases were defined as circumferential or horseshoe configurations, prior diverticulectomy, and/or anti-incontinence procedure. Primary outcome was postoperative SUI. Secondary outcome was interval PVS. Complex and simple cases were compared using the Fisher exact test. RESULTS: Median age was 49 years (interquartile range, 36-58 years). Median follow-up was 5.4 months (IQR, 2-24 months). Thirty of 55 (55%) cases were simple, and 25 of 55 (45%) complex. Preoperative SUI was present in 19/57 (35%) (11 complex vs 8 simple, P = 0.25). Stress urinary incontinence persisted postoperatively in 10 of 19 (52%) (6 complex vs 4 simple, P = 0.48). De novo SUI occurred in 7 of 55, 12% (4 complex vs 3 simple, P = 0.68). Overall, 17 of 55 (31%) patients had postoperative SUI (10 complex vs 7 simple, P = 0.24). Of those, 8 of 17 underwent subsequent PVS placement (P = 0.71) and 9 of 17 had resolution of pad use after physical therapy (P = 0.27). CONCLUSIONS: We did not find evidence of an association between complexity and postoperative SUI. Age at surgery and preoperative frequency were the strongest predictors of postoperative SUI in this cohort. Our findings suggest successful complex urethral diverticulum repair does not require concomitant PVS.

Purely Covalent Molecular Cages and Containers for Guest Encapsulation.

Cage compounds offer unique binding pockets similar to enzyme-binding sites, which can be customized in terms of size, shape, and functional groups to point toward the cavity and many other parameters. Different synthetic strategies have been developed to create a toolkit of methods that allow preparing tailor-made organic cages for a number of distinct applications, such as gas separation, molecular recognition, molecular encapsulation, hosts for catalysis, etc. These examples show the versatility and high selectivity that can be achieved using cages, which is impossible by employing other molecular systems. This review explores the progress made in the field of fully organic molecular cages and containers by focusing on the properties of the cavity and their application to encapsulate guests.

Novel plasma glycoprotein biomarkers predict progression-free survival in surgically resected clear cell renal cell carcinoma.

INTRODUCTION: Limited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS). METHODS: Plasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrell's C-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves. RESULTS: The average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate P ≤ 0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio (HR) of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR = 6.47, P = 9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR = 10.69, P = 0.001), clusterin A2G2 motif (HR = 7.38, P = 0.002), complement component C8A A2G2S2 motif (HR = 11.59, P = 0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR = 6.30, P = 0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9 to 10.7, all with P-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (P < 0.0001). CONCLUSION: Differential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.

Aneurisma de arteria pulmonar: un hallazgo incidental / Pulmonary artery aneurysm: an incidental finding

Resumen Los aneurismas de la arteria pulmonar son entidades infrecuentes y su tratamiento es tema de discusión. Desde el punto de vista etiológico pueden ser congénitos o adquiridos. Los primeros, generalmente se asocian a malformaciones cardiacas que producen hipertensión pulmonar, siendo el ductus arterioso la más frecuente. Otras anomalías incluyen defectos auriculares o ventriculares. Las causas adquiridas pueden ser idiopáticas o estar asociadas a infecciones (tuberculosis, sífilis), traumatismos o colagenopatías. Presentamos el caso de una mujer de 62 años, quien consultó por un cuadro clínico en el que se destacaba su sintomatología neurológica e infecciosa, con posterior progresión a un choque séptico y en quien los hallazgos de las imágenes mostraron un aneurisma gigante de la arteria pulmonar siendo este un hallazgo incidental y sin relación a la sintomatología de la paciente.

Abstract Aneurysms of the pulmonary artery are rare entities and their treatment is a matter of discussion. From the etiological point of view, they can be congenital or acquired. Those in the first group are generally associated with cardiac malformations that generate pulmonary hypertension, with the ductus arteriosus being the most frequent. Other abnormalities include atrial or ventricular defects. The acquired causes may be idiopathic or associated with infections (tuberculosis, syphilis), trauma, or collagen disease. We present the case of a 62-year-old woman, which consulted for a clinical condition where neurological and infectious symptoms stood out, with subsequent progression to a state of septic shock, and in whom the imaging finding showed a giant pulmonary artery aneurysm. this being an incidental finding and unrelated to the patient's symptoms.

Signal transducer and activator of transcription 6 as a target in colon cancer therapy.

Signal transducer and activator of transcription 6 (STAT6) is a member of the STAT family of proteins that serve key roles in the initiation of tumorigenesis and malignant transformation. STAT6 is highly expressed in several types of cancer, including breast, pancreatic, prostate and colorectal cancer. STAT6 transduces signals in response to the binding of interleukin (IL)-4 and IL-13 to their receptors and regulates the expression of genes involved in the immune response, cell survival, tumor proliferation and metastasis. Patients with colorectal cancer exhibit high STAT6 activity in the colonic epithelium, and STAT6 expression is associated with lower survival rates, lymph node metastasis, changes in the epithelial barrier function and alterations in the inflammatory response. A number of studies investigating experimental models and cancer cell lines have revealed that STAT6 is associated with tumor growth and development, as well as with increased invasion and metastasis, suggesting that STAT6 inhibition may serve as a novel therapeutic strategy in colon cancer. The present review summarizes the evidence with regard to the implications of STAT6 in cancer biology and the direct and indirect effects on colon tumor transformation. Furthermore, the current treatment strategies targeting the IL-4/IL-13/STAT6 axis in colon cancer are discussed.

Plasma Levels of Myonectin But Not Myostatin or Fibroblast-Derived Growth Factor 21 Are Associated with Insulin Resistance in Adult Humans without Diabetes Mellitus.

BACKGROUND: Myokines are a group of protein mediators produced by skeletal muscle under stress or physical exertion. Even though their discovery and effects in cell culture and animal models of disease have elicited great enthusiasm, very little is known about their role in human metabolism. We assessed whether plasma concentrations of three known myokines [myonectin, myostatin, and fibroblast-derived growth factor 21 (FGF-21)] would be associated with direct and indirect indicators of insulin resistance (IR) in individuals who did not have a diagnosis of diabetes. METHODS: We studied 81 adults of both sexes comprising a wide range of body adiposity and insulin sensitivity. All participants underwent a thorough clinical assessment and a 5-point oral glucose tolerance test with calculation of multiple IR and insulin sensitivity indices. Twenty-one of them additionally underwent a hyperinsulinemic-euglycemic clamp with determination of steady-state whole-body insulin-stimulated glucose disposal ("M"). We compared plasma myokine concentrations across quartiles of IR indices and clinical IR surrogates, and explored the correlation of each myokine with the M-value. RESULTS: Plasma myonectin levels increased monotonically across quartiles of the incremental area under the insulin curve (higher values indicate more IR) (p-trend = 0.021) and decreased monotonically across quartiles of the insulin sensitivity index (ISI - higher values indicate less IR) (p-trend = 0.012). After multivariate adjustment for other relevant determinants of IR (body mass index, age, and sex), the negative association of myonectin with ISI persisted (standardized beta = -0.235, p = 0.023). Myostatin was not associated with any clinical IR indicator or direct IR index measure. In multivariate analyses, FGF-21 showed a trend toward a positive correlation with glucose disposal that did not reach statistical significance (standardized beta = 0.476, p = 0.091). CONCLUSION: The secretion of myonectin may constitute an attempt at a compensatory mechanism against IR in humans.

Clinical implications of hepatobiliary scintigraphy and ultrasound in the diagnosis of acute cholecystitis.

BACKGROUND: We assess the performance of ultrasound (US) and hepatobiliary scintigraphy (HIDA) as confirmatory studies in acute cholecystitis (AC) and demonstrate our current imaging protocol's impact on outcomes. STUDY DESIGN: Between January 2013 to July 2014, 117 patients were admitted through the emergency room with a preliminary diagnosis of AC. Overall, 106/117 (91%) of the patients received US preadmission and 34/117 (29%) received a HIDA post admission. Primary end points included: 1) diagnostic test reliability for AC, and 2) outcome and quality measures (time to surgery, LOS, costs, etc.). RESULTS: Laparoscopic cholecystectomy was performed in 96/117 (82%) and open cholecystectomy in 21/117 (18%) of the patients. Overall, histopathologic features consistent with AC was present in 46/117 (39%). AC alone was present in 23/117 (20%), and AC superimposed on chronic cholecystitis was present in 23/117 (20%). For AC, US had a sensitivity and specificity of 26% and 80%, respectively. HIDA scan had a sensitivity and specificity of 87% and 79%, respectively. Time to surgery (TTS) was 4 vs 2.3 days in patients who received HIDA vs US alone (p = 0.001), and length of stay (LOS) was 6.7 vs 4.3 days, respectively (p = 0.001). Age >50 years, glucose >140 (mg/dl), and WBC count >10 (×109 /L) were statistically significant independent variables associated with AC. CONCLUSION: HIDA scan is superior to US as a diagnostic study in the setting of AC. Our current protocol of delayed HIDA (post-admission) was associated with increased TTS, LOS, and overall costs. Early confirmation with HIDA in high risk patients may hasten treatment allocation and improve outcomes in the setting of AC.