Stem Cells for Cancer Therapy: Translating the Uncertainties and Possibilities of Stem Cell Properties into Opportunities for Effective Cancer Therapy.

Cancer recurrence and drug resistance following treatment, as well as metastatic forms of cancer, are trends that are commonly encountered in cancer management. Amidst the growing popularity of personalized medicine and targeted therapy as effective cancer treatment, studies involving the use of stem cells in cancer therapy are gaining ground as promising translational treatment options that are actively pursued by researchers due to their unique tumor-homing activities and anti-cancer properties. Therefore, this review will highlight cancer interactions with commonly studied stem cell types, namely, mesenchymal stroma/stem cells (MSC), induced pluripotent stem cells (iPSC), iPSC-derived MSC (iMSC), and cancer stem cells (CSC). A particular focus will be on the effects of paracrine signaling activities and exosomal miRNA interaction released by MSC and iMSCs within the tumor microenvironment (TME) along with their therapeutic potential as anti-cancer delivery agents. Similarly, the role of exosomal miRNA released by CSCs will be further discussed in the context of its role in cancer recurrence and metastatic spread, which leads to a better understanding of how such exosomal miRNA could be used as potential forms of non-cell-based cancer therapy.

Addressing the Clinical Feasibility of Adopting Circulating miRNA for Breast Cancer Detection, Monitoring and Management with Artificial Intelligence and Machine Learning Platforms.

Detecting breast cancer (BC) at the initial stages of progression has always been regarded as a lifesaving intervention. With modern technology, extensive studies have unraveled the complexity of BC, but the current standard practice of early breast cancer screening and clinical management of cancer progression is still heavily dependent on tissue biopsies, which are invasive and limited in capturing definitive cancer signatures for more comprehensive applications to improve outcomes in BC care and treatments. In recent years, reviews and studies have shown that liquid biopsies in the form of blood, containing free circulating and exosomal microRNAs (miRNAs), have become increasingly evident as a potential minimally invasive alternative to tissue biopsy or as a complement to biomarkers in assessing and classifying BC. As such, in this review, the potential of miRNAs as the key BC signatures in liquid biopsy are addressed, including the role of artificial intelligence (AI) and machine learning platforms (ML), in capitalizing on the big data of miRNA for a more comprehensive assessment of the cancer, leading to practical clinical utility in BC management.

Modification of the effects of intensive systolic blood pressure control on kidney outcomes by baseline body mass index.

AIM: Obesity and intensive systolic blood pressure (SBP) control are independently associated with greater risk of acute kidney injury (AKI) and incident chronic kidney disease (CKD). We examined whether baseline body mass index (BMI) modifies the effects of intensive SBP lowering on AKI or incident CKD. METHODS: The systolic blood pressure intervention trial (SPRINT) randomized 9361 participants with high blood pressure to an SBP target of either <120 mm Hg or < 140 mm Hg. In a secondary analysis of 9210 SPRINT participants with a baseline BMI of ≥18.5 and < 50 kg/m2 , we examined the interactions of baseline BMI and SPRINT SBP intervention on subsequent AKI and incident CKD. RESULTS: Each 5 kg/m2 increase in baseline BMI was associated with higher risk of AKI (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.01 to 1.25) and incident CKD (HR 1.17, 95% CI 1.01 to 1.32). Intensive SBP control increased the risk of AKI (HR 1.68, 95% CI 1.22-2.11) and incident CKD (HR 3.49, 95% CI 2.47-4.94). The increased risk of AKI with intensive SBP control was consistent across the baseline BMI spectrum (linear interaction p = 0.55); however, the risk of incident CKD with SPRINT intervention increased with higher BMI (linear interaction p = 0.043). CONCLUSION: The increased risk of adverse kidney events seen with intensive SBP control in the SPRINT persisted across the baseline BMI spectrum. A higher baseline BMI was associated with an augmented risk of incident CKD with intensive SBP control.

Formulation, Characterization and Biological Activity Screening of Sodium Alginate-Gum Arabic Nanoparticles Loaded with Curcumin.

The approach of drug delivery systems emphasizes the use of nanoparticles as a vehicle, offering the optional property of delivering drugs as a single dose rather than in multiple doses. The current study aims to improve antioxidant and drug release properties of curcumin loaded gum Arabic-sodium alginate nanoparticles (Cur/ALG-GANPs). The Cur/ALG-GANPs were prepared using the ionotropic gelation technique and further subjected to physico-chemical characterization using attenuated total reflectance-Fourier transform infrared (ATR-FTIR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), size distribution, and transmission electron microscopy (TEM). The size of Cur/ALG-GANPs ranged between 10 ± 0.3 nm and 190 ± 0.1 nm and the zeta potential was -15 ± 0.2 mV. The antioxidant study of Cur/ALG-GANPs exhibited effective radical scavenging capacity for 1,1-diphenyl-2-picrylhydrazyl (DPPH) at concentrations that ranged between 30 and 500µg/mL. Cytotoxicity was performed using MTT assay to measure their potential in inhibiting the cell growth and the result demonstrated a significant anticancer activity of Cur/ALG-GANPs against human liver cancer cells (HepG2) than in colon cancer (HT29), lung cancer (A549) and breast cancer (MCF7) cells. Thus, this study indicates that Cur/ALG-GANPs have promising anticancer properties that might aid in future cancer therapy.

Surgical Treatment of Late Developmental Dysplasia of the Hip in Bladder Exstrophy: A Case Report.

CASE: We present a case of an 8-year-old boy with classical bladder exstrophy and a neglected right hip dislocation, exemplifying the risk of missed developmental dysplasia of the hip (DDH) in patients with exstrophy requiring careful orthopaedic oversight. CONCLUSIONS: When treating patients with bladder exstrophy, physicians and surgeons should be vigilant not to miss associated DDH. If this condition requires surgical treatment, preoperative planning with computed tomography scans is vital to uncovering the complexities arising from abnormal pelvic and acetabular anatomy and ensuring successful treatment outcomes.

Clinical performance of AI-integrated risk assessment pooling reveals cost savings even at high prevalence of COVID-19.

Individual testing of samples is time- and cost-intensive, particularly during an ongoing pandemic. Better practical alternatives to individual testing can significantly decrease the burden of disease on the healthcare system. Herein, we presented the clinical validation of Segtnan™ on 3929 patients. Segtnan™ is available as a mobile application entailing an AI-integrated personalized risk assessment approach with a novel data-driven equation for pooling of biological samples. The AI was selected from a comparison between 15 machine learning classifiers (highest accuracy = 80.14%) and a feed-forward neural network with an accuracy of 81.38% in predicting the rRT-PCR test results based on a designed survey with minimal clinical questions. Furthermore, we derived a novel pool-size equation from the pooling data of 54 published original studies. The results demonstrated testing capacity increase of 750%, 60%, and 5% at prevalence rates of 0.05%, 22%, and 50%, respectively. Compared to Dorfman's method, our novel equation saved more tests significantly at high prevalence, i.e., 28% (p = 0.006), 40% (p = 0.00001), and 66% (p = 0.02). Lastly, we illustrated the feasibility of the Segtnan™ usage in clinically complex settings like emergency and psychiatric departments.

Current developments and therapeutic potentials of exosomes from induced pluripotent stem cells-derived mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are multipotent cells derived from adult human tissues that have the ability to proliferate in vitro and maintain their multipotency, making them attractive cell sources for regenerative medicine. However, MSCs reportedly show limited proliferative capacity with inconsistent therapeutic outcomes due to their heterogeneous nature. On the other hand, induced pluripotent stem cells (iPSC) have emerged as an alternative source for the production of various specialized cell types via their ability to differentiate from all three primary germ layers, leading to applications in regenerative medicine, disease modeling, and drug therapy. Notably, iPSCs can differentiate into MSCs in monolayer, commonly referred to as induced mesenchymal stem cells (iMSCs). These cells show superior therapeutic qualities compared with adult MSCs as the applications of the latter are restricted by passage number and autoimmune rejection when applied in tissue regeneration trials. Furthermore, increasing evidence shows that the therapeutic properties of stem cells are a consequence of the paracrine effects mediated by their secretome such as from exosomes, a type of extracellular vesicle secreted by most cell types. Several studies that investigated the potential of exosomes in regenerative medicine and therapy have revealed promising results. Therefore, this review focuses on the recent findings of exosomes secreted from iMSCs as a potential noncell-based therapy.

Physicochemical characterization and cancer cell antiproliferative effect of silver-doped magnesia nanoparticles.

Silver-doped magnesia nanoparticles (Ag/MgO) were synthesized using the precipitation method and characterized by various techniques such as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA), Brunner-Emmett-Teller (BET) surface area measurements, and dispersive X-ray spectroscopy (EDX). The morphology of Ag/MgO nanoparticles was determined by transmission and scanning electron microscopy, which revealed cuboidal shaped nanoparticles with sizes ranging from 31 to 68 nm and an average size of 43.5 ± 10.6 nm. The anticancer effects of Ag/MgO nanoparticles were evaluated on human colorectal (HT29) and lung adenocarcinoma (A549) cell lines, and their caspase-3, -8, and -9 activities, as well as Bcl-2, Bax, p53, cytochrome C protein expressions were estimated. Ag/MgO nanoparticles showed selective toxicity towards HT29 and A549 cells while remaining relatively innocuous towards the normal human colorectal, CCD-18Co, and lung, MRC-5 cells. The IC50 values of Ag/MgO nanoparticles on the HT29 and A549 cells were found to be 90.2 ± 2.6 and 85.0 ± 3.5 µg/mL, respectively. The Ag/MgO nanoparticles upregulated caspase-3 and -9 activities, downregulated Bcl-2, upregulated Bax and p53 protein expressions in the cancer cells. The morphology of the Ag/MgO nanoparticle treated HT29 and A549 cells was typical of apoptosis, with cell detachment, shrinkage, and membrane blebbing. The results suggest that Ag/MgO nanoparticles induce apoptosis in cancer cells and exhibit potential as a promising anticancer agent.

Recent Advances in the Therapeutic Strategies of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is one of the most common, most formidable, and deadliest malignant types of primary astrocytoma with a poor prognosis. At present, the standard of care includes surgical tumor resection, followed by radiation therapy concomitant with chemotherapy and temozolomide. New developments and significant advances in the treatment of GBM have been achieved in recent decades. However, despite the advances, recurrence is often inevitable, and the survival of patients remains low. Various factors contribute to the difficulty in identifying an effective therapeutic option, among which are tumor complexity, the presence of the blood-brain barrier (BBB), and the presence of GBM cancer stem cells, prompting the need for improving existing treatment approaches and investigating new treatment alternatives for ameliorating the treatment strategies of GBM. In this review, we outline some of the most recent literature on the various available treatment options such as surgery, radiotherapy, cytotoxic chemotherapy, gene therapy, immunotherapy, phototherapy, nanotherapy, and tumor treating fields in the treatment of GBM, and we list some of the potential future directions of GBM. The reviewed studies confirm that GBM is a sophisticated disease with several challenges for scientists to address. Hence, more studies and a multimodal therapeutic approach are crucial to yield an effective cure and prolong the survival of GBM patients.

The epidemiological association of altitude with chronic kidney disease: Evidence of protective effect.

AIMS: We sought to determine the association between living at high altitudes and the estimated glomerular filtration rate (eGFR) and also to determine the prevalence of end-stage renal disease (ESRD) at various altitudes. METHODS: In the first part of the study, we used data from the National Health and Nutrition Examination Survey III to examine the association between altitude of residence and eGFR. In the second part, we used the United States Renal Data System to study the association between altitude and prevalence of ESRD. The query revealed an ESRD prevalence of 485,012 for the year 2005. The prevalence rates were merged with the zip codes dataset. RESULTS: The mean eGFR was significantly increased at higher altitudes (78.4 ± 21.6 vs 85.4 ± 26.8 mL/min for categories 1 and 5, respectively; P < 0.05). In the analysis of the United States Renal Data System data for prevalence of ESRD, we found a significantly lower prevalence at the altitude of 523 feet and higher. CONCLUSION: Using a population-based approach, our study demonstrates an association between altitude and renal function. This association is independent of all factors studied and is reached at approximately 250 feet. There is also a negative association between the prevalence of ESRD and altitude of residence. Further studies are needed to elucidate the pathophysiological basis of these epidemiological findings.

Page kidney phenomenon in kidney allograft following abdominal trauma.

The page kidney phenomenon is often associated in patients with abdominal trauma. External compression from a renal hematoma can cause hypertension, and presentation can be delayed following the initial injury. For patients who have a kidney allograft, page kidneys may lead to renal insufficiency and acute renal failure due to the absence of a contralateral kidney to compensate. This case report discusses the identification and management of a page kidney in a kidney allograft recipient within three months following transplantation.

Potential effect of olanzapine on total antioxidant status and lipid peroxidation in schizophrenic patients.

Olanzapine is an atypical antipsychotic drug used in the treatment of schizophrenia. Controversial results have been obtained measuring different serum antioxidant enzymes and serum malondialdehyde (MDA) in schizophrenic patients treated with olanzapine. The aim of this study is to find the effect of olanzapine on total antioxidant status (TAS) and lipid peroxidation in schizophrenic patients. Thirty schizophrenic patients were treated orally with olanzapine (10-20 mg/day) for 2 months. Thirty healthy subjects were also included as a control group. Blood samples were taken from patients before and after olanzapine therapy, and analyzed for serum TAS and MDA. In schizophrenic patients, mean values of pretreatment serum TAS were significantly less (difference = 37.4% of control) than the control value, whereas serum MDA levels were significantly higher (difference = 176% of control) than the control values . Olanzapine treatment for 2 months significantly increased serum TAS levels (37.8%) and reduced serum MDA levels (22.2%) in comparison to respective pretreatment values. In conclusion, the data suggest that olanzapine therapy for 2 months at least partially ameliorates adverse effects on the antioxidant defense mechanism in schizophrenia.

Evaluation of CERS2 Gene as a Potential Biomarker for Bladder Cancer.

The ceramide synthase 2 (CERS2) gene has been linked to tumour recurrence and invasion in many different types of cancers including bladder cancer. In this study, the expression levels of CERS2 in bladder cancer cell lines were analysed using qRT-PCR and the protein expression in clinical bladder cancer histopathological specimens were examined via immunohistochemistry. The potential utility of CERS2 as a predictive biomarker of response to oncolytic virotherapy was assessed by correlating the CERS2 mRNA expression to IC50 values of cells treated with the Newcastle disease virus (NDV), AF2240 strain. This study demonstrates that CERS2 is differentially expressed in different types of bladder cancer cell lines and that the siRNA-mediated downregulation of the expression of CERS2 reduces the migratory potential of UMUC1 bladder cancer cells. However, there were no significant correlations between the expression levels of the CERS2 protein with bladder cancer grade/stage or between the IC50 values of cells treated with NDV and CERS2 expression. Although the utility of CERS2 expression may be limited, its potential as an antimigration cancer therapeutic should be further examined.

De novo immune complex deposition in kidney allografts: a series of 32 patients.

Immune complex deposition in kidney allografts can include both recurrent and de novo processes. Recurrent glomerulonephritis is a well-recognized phenomenon and has been shown to be a common cause of allograft failure. De novo immune complex-mediated disease remains relatively poorly characterized, likely owing to the less frequent use of immunofluorescence and electron microscopy in the transplant setting. We performed a retrospective review of kidney allograft biopsies showing glomerular immune complex deposition. Cases with de novo deposits were identified and further organized into two groups depending on whether the immune complex deposition could be clinically and/or histologically classified. Thirty-two patients with de novo immune complex deposition were identified over a 7-year period. A broad range of immune complex-mediated injuries were observed, the majority (63%) of which could be readily classified either clinically or histologically. These included cases of membranous glomerulonephropathy, IgA nephropathy, infection-related glomerulonephritis and glomerulonephritis related to an underlying autoimmune process. A smaller subset of patients (37%) demonstrated immune complex deposition that was difficult to histologically or clinically classify. These patients typically showed mild mesangial immune complex deposition with co-dominant IgG and IgM staining by immunofluorescence microscopy. The presence of concurrent antibody-mediated rejection and donor-specific antibody positivity was significantly higher in the unclassifiable group. The significance of these deposits and their possible relationship to allograft rejection deserves further investigation.

Splenectomy vs. rituximab as a second-line therapy in immune thrombocytopenic purpura: a single center experience.

Immune thrombocytopenic purpura (ITP) is a common hematological disease treated primarily by corticosteroids. The aim of the present study was to compare response rate between patients, underwent splenectomy vs. rituximab as second-line therapy. Adult patients diagnosed with ITP who did not respond to corticosteroids or relapsed during the period 1990-2014 were included in a quasi-experimental study. Categorical variables were compared using Fisher exact test. Response to treatment was compared using logistic regression. Data were analyzed using SAS V9.2. One-hundred and forty-three patients with ITP were identified through medical records. Of 62 patients treated, 30 (48.38%) required second-line therapy. 19 (63%) patients received rituximab, and 11 (37%) underwent splenectomy. Platelets at diagnosis were not different between study groups (p = 0.062). Splenectomy group patients were younger (p = 0.011). Response to second-line therapy showed no significant difference between two groups (OR 2.03, 95% CI (0.21-22.09), p = 0.549). Results did not show a statistically significant difference in platelet counts over time between treatment groups (p = 0.101). When used exclusively as a second-line therapy for steroid-refractory ITP, the response rate was not statistically different between rituximab and splenectomy. However, further large studies are needed to assess the response rates for these treatment modalities as a second-line therapy.

Early Results of Pilot Study Using Hepatitis C Virus (HCV) Positive Kidneys to Transplant HCV Infected Patients with End-Stage Renal Disease Allowing for Successful Interferon-Free Direct Acting Antiviral Therapy after Transplantation.

INTRODUCTION: Hepatitis C virus (HCV) infection in kidney transplant (KTX) patients reduces long-term patient and graft survival. Direct-acting antivirals (DAA) are > 90% effective in achieving sustained viral response (SVR); however, DAAs are not routinely available to patients with end-stage renal disease (ESRD). The University of Utah Transplant Program developed a protocol to allow HCV-positive potential KTX recipients to accept HCV-positive donors' kidneys. Three months after successful KTX, they were eligible for DAA therapy. METHODS: HCV-positive patients approved for KTX by the University of Utah Transplant Selection Committee were eligible to be enrolled in this study. Patients consented for the use of HCV-positive donor organs. Three to six months after successful KTX, these patients were treated for HCV with interferon-free direct-acting antiviral regimens according to viral genotype and prior treatment experience. RESULTS: Between 2014-2015, 12 HCV-positive patients were listed for KTX. Eight patients were kidney only eligible, seven patients received HCV-positive deceased donor kidneys, and one received an HCV-negative organ. Currently, six patients have completed treatment, all have achieved sustained viral response (SVR), and one patient is currently awaiting treatment. All seven patients have functioning kidney grafts. Wait time for KTX was reduced amongst all blood groups from an average of 1,350 days to only 65 days. CONCLUSIONS: HCV-positive patients with ESRD can successfully receive an HCV-positive donor's kidney. Once transplanted, these patients can receive DAA therapy and achieve SVR. Use of HCV-positive organs reduced time on the waitlist by greater than three years and expanded the donor organ pool.

Asymmetric dimethylarginine and whole blood viscosity in renal failure.

BACKGROUND: Renal failure is a disease with accelerated atherosclerosis beginning with endothelial cell dysfunction. Factors affecting endothelial cell dysfunction include whole blood viscosity (WBV) and asymmetric dimethylarginine (ADMA). The relationship in controls and renal failure was determined. METHODS: 51 subjects, 20 controls, 11 renal transplant recipients, 10 chronic kidney disease and 10 end-stage renal disease patients had blood samples drawn for WBV, Hematocrit, and ADMA. WBV was measured at various shear rates from 10 s(-1) to 780 s(-1) at 37 °C. Hematocrit using CritSpin, and ADMA was assayed using an ELISA method. The significance between groups was compared by boxplots and analysis of variance. Linear relationships were shown by regression lines and correlation coefficients. RESULTS: ADMA was elevated in all groups with renal failure when compared to controls (p < 0.05). Control subjects showed a positive correlation between ADMA and WBV, while those who received a renal transplant had a negative correlation (p < 0.05). The difference in ADMA comparing pre-dialysis to post-dialysis conditions was positive (p < 0.05). CONCLUSIONS: The positive relationship between WBV and ADMA in controls is a novel finding and allows for comparison with other groups. This relationship is dramatically altered in renal failure.