A novel treatment strategy utilizing panobinostat for high-risk and treatment-refractory hepatoblastoma.

BACKGROUND & AIMS: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition. METHODS: RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen. RESULTS: HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC50 of 0.013-0.059 µM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups. CONCLUSIONS: Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB. IMPACT AND IMPLICATIONS: Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials.

Code Status Orders: Do the Options Matter?

BACKGROUND: Code status orders in hospitalized patients guide urgent medical decisions. Inconsistent terminology and treatment options contribute to varied interpretations. OBJECTIVE: To compare two code status order options, traditional (three option) and modified to include additional care options (four option). DESIGN: Prospective, randomized, cross-sectional survey conducted on February-March 2020. Participants were provided with six clinical scenarios and randomly assigned to the three or four option code status order. In three scenarios, participants determined the most appropriate code status. Three scenarios provided clinical details and code status and respondents were asked whether they would provide a particular intervention. This study was conducted at three urban, academic hospitals. PARTICIPANTS: Clinicians who routinely utilize code status orders. Of 4006 participants eligible, 549 (14%) were included. MAIN MEASURES: The primary objective was consensus (most commonly selected answer) based on provided code status options. Secondary objectives included variables associated with participant responses, participant code status model preference, and participant confidence about whether their selections would match their peers. KEY RESULTS: In the three scenarios participants selected the appropriate code status, there was no difference in consensus for the control scenario, and higher consensus in the three option group (p-values < 0.05) for the remaining two scenarios. In the scenarios to determine if a clinical intervention was appropriate, two of the scenarios had higher consensus in the three option group (p-values 0.018 and < 0.05) and one had higher consensus in the four option group (p-value 0.001). Participants in the three option model were more confident that their peers selected the same code status (p-value 0.0014); however, most participants (72%) preferred the four option model. CONCLUSIONS: Neither code status model led to consistent results. The three option model provided consistency more often; however, the majority of participants preferred the four option model.

Partnership development of the COVID-19 Front Door: a best evidence resource.

This project describes the creation of a single searchable resource during the pandemic, called the COVID-19 Best Evidence Front Door, with a primary goal of providing direct access to high-quality meta-analyses, literature syntheses, and clinical guidelines from a variety of trusted sources. The Front Door makes relevant evidence findable and accessible with a single search to aggregated evidence-based resources, optimizing time, discovery, and improved access to quality scientific evidence while reducing the burden of frontline health care providers and other knowledge-seekers in needing to separately identify, locate, and explore multiple websites.

Role of nanowire length on the performance of a self-driven NIR photodetector based on mono/bi-layer graphene (camphor)/Si-nanowire Schottky junction.

In this article, we have demonstrated a solid carbon source such as camphor as a natural precursor to synthesize a large area mono/bi-layer graphene (MLG) sheet to fabricate a nanowire junction-based near infrared photodetectors (NIRPDs). In order to increase the surface-to-volume ratio, we have developed Si-nanowire arrays (SiNWAs) of varying lengths by etching planar Si. Then, the camphor-based MLG/Si and MLG/SiNWAs Schottky junction photodetectors have been fabricated to achieve an efficient response with self-driven properties in the near infrared (NIR) regime. Due to a balance between light absorption capability and surface recombination centers, devices having SiNWAs obtained by etching for 30 min shows a better photoresponse, sensitivity and detectivity. Fabricated NIRPDs can also be functioned as self-driven devices which are highly responsive and very stable at low optical power signals up to 2 V with a fast rise and decay time of 34/13 ms. A tremendous enhancement has been witnessed from 36 µA W-1 to 22 mA W-1 in the responsivity at 0 V for MLG/30 min SiNWAs than planar MLG/Si PDs indicating an important development of self-driven NIRPDs based on camphor-based MLG for future optoelectronic devices.

ß-cell replenishment: Possible curative approaches for diabetes mellitus.

AIMS: Diabetes mellitus (DM) is a disorder of heterogeneous etiology marked by persistent hyperglycemia. Exogenous insulin is the only treatment for type 1 diabetes (T1D). Islet transplantation is a potential long cure for T1D but is disapproved due to the possibility of immune rejection in the later stage. The approaches used for treating type 2 diabetes (T2D) include diet restrictions, weight management and pharmacological interventions. These procedures have not been able to boost the quality of life for diabetic patients owing to the complexity of the disorder. DATA SYNTHESIS: Hence, research has embarked on permanent ways of managing, or even curing the disease. One of the possible approaches to restore the pancreas with new glucose-responsive ß-cells is by their regeneration. Regeneration of ß-cells include islet neogenesis, dedifferentiation, and trans-differentiation of the already differentiated cells. CONCLUSIONS: This review briefly describes the islet development, functions of ß-cells, mechanism and factors involved in ß-cell death. It further elaborates on the potential of the existing and possible therapeutic modalities involved in the in-vivo replenishment of ß-cells with a focus on exercise, diet, hormones, small molecules, and phytochemicals.

Genetic variants of resistin and its plasma levels: Association with obesity and dyslipidemia related to type 2 diabetes susceptibility.

Resistin, an adipokine, is involved in obesity and Type 2 Diabetes (T2D). The current study evaluates the association between RETN polymorphisms (-638 G/A, -420C/G & -358 G/A) and the risk towards T2D. Controls and T2D patients were enrolled from Gujarat, India. Polymorphisms of RETN were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. For the genotype-phenotype correlation analysis Fasting Blood Glucose (FBG), Body Mass Index (BMI) and plasma lipid profile were used. Plasma levels of resistin were assayed by ELISA. Our study suggests an association of RETN -420C/G polymorphism with T2D risk. The CC genotype of RETN -420C/G polymorphism was found to be associated with FBG, BMI, and total cholesterol. Plasma resistin levels were found to be significantly increased in diabetic patients as compared to controls. Our findings suggest -420C/G polymorphism of RETN as an important factor which could pose a powerful risk towards T2D susceptibility.

The Effect of Heat Shock Protein 90 Inhibitor on Pain in Cancer Patients: A Systematic Review and Meta-Analysis.

Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an essential role in tumor growth. Numerous Hsp90 inhibitors have been discovered and tested in preclinical and clinical trials. Recently, several preclinical studies have demonstrated that Hsp90 inhibitors could modulate pain sensitization. However, no studies have evaluated the impact of Hsp90 inhibitors on pain in the patients. This study aims to summarize the pain events reported in clinical trials assessing Hsp90 inhibitors and to determine the effect of Hsp90 inhibitors on pain in patients. We searched PubMed, EBSCOhost, and clinicaltrials.gov for Hsp90 inhibitor clinical trials. The pain-related adverse events were summarized. Meta-analysis was performed using the data reported in randomized controlled trials. We identified 90 clinical trials that reported pain as an adverse effect, including 5 randomized controlled trials. The most common types of pain reported in all trials included headache, abdominal pain, and back pain. The meta-analysis showed that Hsp90 inhibitors increased the risk of abdominal pain significantly and appeared to increase the risk for back pain. In conclusion, Hsp90 inhibitor treatment could potentially increase the risk of pain. However, the meta-analysis demonstrated only moderate evidence for the connection between Hsp90 inhibitor and pain.

Circulatory Omentin-1 levels but not genetic variants influence the pathophysiology of Type 2 diabetes.

OBJECTIVE: Omentin-1, an anti-inflammatory protein, is secreted by the visceral adipose tissue. Altered levels of Omentin-1 are associated with obesity and Type 2 Diabetes (T2D). Although Omentin-1 is implicated in the insulin signaling pathway, the relationship between the genetic variants of Omentin-1 and T2D is not yet explored. The current study evaluates the association of Omentin-1 polymorphisms (rs2274907 A/T and rs1333062 G/T), its transcript and protein levels, and genotype-phenotype correlation with metabolic parameters and T2D susceptibility. METHODS: Plasma and Peripheral Blood Mononuclear Cells (PBMCs) were separated from venous blood taken from 250 controls and 250 T2D patients recruited from Gujarat, India. Genomic DNA was isolated from PBMCs and genotyping of Omentin-1 variants was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). RNA was isolated from Visceral Adipose Tissue (VAT) samples of 12 controls and 10 patients, and transcript levels of Omentin-1 were assessed by qPCR. Plasma Omentin-1 levels were estimated by ELISA. Fasting Blood Glucose, Body Mass Index (BMI) and plasma lipid profile were considered for the genotype-phenotype correlation analysis. RESULTS: Our study revealed no association of Omentin-1 genetic variants with T2D risk (p > 0.05). However, the AT genotype of Omentin-1 rs2274907 A/T polymorphism was associated with increased BMI (p = 0.0247). Plasma Omentin-1 levels were significantly decreased (p < 0.0001) however, increased VAT Omentin-1 transcript levels (p = 0.0127) were observed in T2D patients. CONCLUSION: Our findings suggest that decreased circulatory Omentin-1 levels could pose a risk towards T2D susceptibility.

Seventy-two-hour antibiotic retrieval from the ED: a randomized controlled trial of discharge instructional modality.

BACKGROUND: Limited health literacy is a risk factor for poor outcomes in numerous health care settings. Little is known about the impact of instructional modality and health literacy on adherence to emergency department (ED) discharge instructions. PURPOSE: To examine the impact of instructional modality on 72-hour antibiotic retrieval among ED patients prescribed outpatient antibiotics for infections. METHODS: English-speaking ED patients diagnosed as having acute infections and prescribed outpatient antibiotics were randomized to standard discharge instructions, standard instructions plus text-messaged instructions, or standard instructions plus voicemailed instructions targeting ED prescriptions. Health literacy was determined by validated instrument. Seventy-two-hour antibiotic retrieval, 30-day report of prescription completion, and discharge instructional modality preference were assessed. RESULTS: Nearly one-quarter of the 2521 participants demonstrated low health literacy. Low health literacy predicted decreased 72-hour antibiotic retrieval (χ(2) = 9.56, P=.008). No significant association with antibiotic retrieval was noted across the 3 treatment groups (χ(2) = 5.112, P=.078). However, patients randomized to the text message group retrieved antibiotic prescriptions within 72 hours more frequently than did those randomized to the voicemail treatment group (χ(2) = 4.345, P=.037), and patients with low health literacy randomized to voicemailed instructions retrieved their antibiotic prescriptions less frequently than did those randomized to standard of care instructions (χ(2) = 5.526, P=.019). Reported instructional modality preferences were inconsistent with the primary findings of the study. CONCLUSIONS: Discharge instructional modality impacts antibiotic retrieval in patients with low health literacy. Preference for discharge instructional modality varies by degree of health literacy, but does not predict which modality will optimize 72-hour antibiotic retrieval.

mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling.

High-risk neuroblastoma often develops resistance to high-dose chemotherapy. The mTOR signaling cascade is frequently deregulated in human cancers and targeting mTOR signaling sensitizes many cancer types to chemotherapy. Here, using a panel of neuroblastoma cell lines, we found that the mTOR inhibitor INK128 showed inhibitory effects on both anchorage-dependent and independent growth of neuroblastoma cells and significantly enhanced the cytotoxic effects of doxorubicin (Dox) on these cell lines. Treatment of neuroblastoma cells with INK128 blocked the activation of downstream mTOR signaling and enhanced Dox-induced apoptosis. Moreover, INK128 was able to overcome the established chemoresistance in the LA-N-6 cell line. Using an orthotopic neuroblastoma mouse model, we found that INK128 significantly inhibited tumor growth in vivo. In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Dox therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma.

A comparison of routine, opt-out HIV screening with the expected yield from physician-directed HIV testing in the ED.

OBJECTIVES: The Centers for Disease Control and Prevention recommends routine opt-out HIV screening in health care settings. Our goal was to evaluate the feasibility and yield of this strategy in the emergency department (ED) and to compare it to the expected yield of physician-directed testing. METHODS: This is a cross-sectional study in an urban ED during random shifts over 1 year. Patients were ineligible for screening if they were younger than 18 years or older than 64, a prisoner, a victim of sexual assault, in an ED resuscitation room, or had altered mental status. Research associates administered rapid HIV tests and conducted standardized interviews. The patients' ED physician, blinded to the HIV result, was asked if they would have ordered a rapid HIV test if it had been available. RESULTS: Of 7756 ED patients, 3957 (51%) were eligible for HIV screening, and 2811 (71%) of those did not opt out. Routine testing yielded 9 new HIV cases (0.32% of those tested; 95% confidence interval, 0.16%-0.63%). Physician-directed testing would have missed most of these infections: 2 of the 785 patients identified by physicians for testing would have been newly diagnosed with HIV (0.25%; 95% confidence interval, 0.04%-1.0%). Of the 9 new HIV cases, 5 established HIV care, and their median CD4 count was 201 cells/µL (range, 71-429 cells/µL). CONCLUSIONS: Routine opt-out HIV screening was feasible and accepted by a majority of ED patients. The yield of this strategy only modestly exceeded what may have been observed with physician-directed testing.

Access to disease treatment among patients presenting to the emergency department with asthma or hypertension.

BACKGROUND: Asthma and hypertension are common among Emergency Department (ED) patients. Primary care providers are integral in managing these conditions, yet these patients are often in the ED. OBJECTIVE: To determine access to care among ED patients with asthma or hypertension and the association with sociodemographic factors and disease acuity. METHODS: This was a prospective, cross-sectional study of ED patients at an urban county hospital conducted between June 4 and August 31, 2008. Consenting patients were surveyed, and peak flow or blood pressure measured as appropriate. Access to disease treatment was defined as self-reported access to a primary care provider or current prescription for asthma or hypertension, or both. Descriptive statistics and multinomial logistic regression were used to analyze data. RESULTS: There were 2303 patients enrolled; 283 had asthma, 543 had hypertension, and 187 had both. Seventy-one patients (25.1%) with asthma, 151 patients (27.8%) with hypertension, and 19 patients (10.2%) with both had poor access to disease treatment. Seeking ED medical attention was related to having poor access to treatment for patients with both asthma and hypertension. Females with asthma had poor access to treatment. In hypertension patients, good access to treatment was associated with excellent/good health status, housing status, and decreasing age. Poor access to treatment was associated with increasing blood pressure. CONCLUSIONS: Poor access to disease treatment and aspects of socioeconomic status were associated with seeking care in the ED. Changes in access to treatment may affect the number of patients seeking ED care, but not the severity of the presenting illness.

Histopathologic and immunophenotypic characterization of patient-derived pediatric malignant hepatocellular tumor xenografts (PDXs).

Advances in targeted therapies for pediatric hepatocellular tumors have been limited due to a paucity of clinically relevant models. Establishment and validation of intrahepatic patient-derived xenograft (PDX) models would help bridging this gap. The aim of this study is to compare the histomorphologic and immunophenotypic fidelity of patient tumors and their corresponding intrahepatic PDX models. Murine PDX models were established by intrahepatic implantation of patient tumors. Pathology slides from both patients and their corresponding PDX models were reviewed and quantitatively assessed for various histologic components and immunophenotypic markers. Ten PDX models were successfully established from nine patients with pre- (n=3) and post- (n=6) chemotherapy samples; diagnosed of hepatoblastoma (n=8) and hepatocellular neoplasm, not otherwise specified (n=1). Two of nine (22.2%) patients showed ≥75% fetal component; however, the corresponding PDX models did not maintain this fetal differentiation. High grade histology was seen in three patients (33.3%) and overrepresented in six PDX models (60%). Within the subset of three PDXs that were further characterized, significant IHC concordance was seen in all 3 models for CK7, CK19, Ki-67, and p53; and 2 of 3 models for Sox9 and Beta-catenin. GPC-3 and GS showed variable to moderate concordance, while Hepar was the least concordant. Our study shows that in general, the PDX models appear to represent the higher-grade component of the original tumor and show significant concordance for Ki-67, making them appropriate tools for testing new therapies for the most aggressive, therapy-resistant tumors.

An indocyanine green-based liquid biopsy test for circulating tumor cells for pediatric liver cancer.

BACKGROUND: Hepatoblastoma and HCC are the most common malignant hepatocellular tumors seen in children. The aim of this study was to develop a liquid biopsy test for circulating tumor cells (CTCs) for these tumors that would be less invasive and provide real-time information about tumor response to therapy. METHODS: For this test, we utilized indocyanine green (ICG), a far-red fluorescent dye used clinically to identify malignant liver cells during surgery. We assessed ICG accumulation in cell lines using fluorescence microscopy and flow cytometry. For our CTC test, we developed a panel of liver tumor-specific markers, including ICG, Glypican-3, and DAPI, and tested it with cell lines and noncancer control blood samples. We then used this panel to analyze whole-blood samples for CTC burden with a cohort of 15 patients with hepatoblastoma and HCC and correlated with patient characteristics and outcomes. RESULTS: We showed that ICG accumulation is specific to liver cancer cells, compared to nonmalignant liver cells, non-liver solid tumor cells, and other nonmalignant cells, and can be used to identify liver tumor cells in a mixed population of cells. Experiments with the ICG/Glypican-3/DAPI panel showed that it specifically tagged malignant liver cells. Using patient samples, we found that CTC burden from sequential blood samples from the same patients mirrored the patients' responses to therapy. CONCLUSIONS: Our novel ICG-based liquid biopsy test for CTCs can be used to specifically detect and quantify CTCs in the blood of pediatric patients with liver cancer.

TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy.

Treatment failure in high risk neuroblastoma is largely due to development of chemoresistance. NF-κB activation is one of the resistance mechanisms for cancer cells to escape from chemotherapy-induced cell-death. TAK1 is an essential component in genotoxic stresses-induced NF-κB activation; however, the role of TAK1 in the development of chemoresistance in neuroblastoma remains unknown. Using a panel of neuroblastoma cell lines, we found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) on neuroblastoma cell lines. TAK1 inhibition also enhanced the inhibitory effect of Dox and VP-16 on anchorage-independent growth. Treatment of neuroblastoma cells with 5Z-7-oxozeaenol blocked Dox- and VP16-induced NF-κB activation and enhanced Dox- and VP16-induced apoptosis. Moreover, 5Z-7-oxozeaenol was able to overcome the established chemoresistance in LA-N-6 neuroblastoma cells. Using an orthotopic neuroblastoma mouse model, we found that 5Z-7-oxozeaenol significantly enhanced chemotherapeutic efficacy in vivo. Together, our results provide a proof-of-concept that TAK1 inhibition significantly increases the sensitivity of neuroblastoma cells to chemotherapy-induced cell-death and can serve as an effective adjunct to current chemotherapeutic regimens for high risk diseases.

Adult onset nesidioblastosis treated by subtotal pancreatectomy.

CONTEXT: Nesidioblastosis is a rare cause of non insulinoma pancreatogenous hypoglycemic syndrome seen in adults. It is characterized by postprandial hypoglycemia with high insulin and C-peptide levels without any detectable pancreatic lesion. The definitive diagnosis can be made only on histopathological examination of the resected specimen. CASE REPORT: We report a case of a 50-year-old lady presenting with hypoglycemic attacks being misdiagnosed preoperatively as insulinoma and treated with enucleation leading to recurrence of symptoms after 6 months. Later medical therapy was tried which failed and patient needed subtotal pancreatectomy for resolution of symptoms. CONCLUSION: Nesidioblastosis should be suspected in patients with endogenous hyperinsulinemic hypoglycemia without any detectable pancreatic tumor on preoperative imaging.

Repurposing Pitavastatin and L-Glutamine: Replenishing ß-Cells in Hyperlipidemic Type 2 Diabetes Mouse Model.

Type 2 diabetes (T2D) is associated with obesity and declining ß-cells. L-glutamine has been implicated in the amelioration of T2D by virtue of its incretin secretagogue property while, there are mixed reports on pitavastatin's adiponectin potentiating ability. We aimed to investigate the effect of pitavastatin (P), L-glutamine (LG), and combination (P + LG) on glycemic control and ß-cell regeneration in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2D mouse model. C57BL6/J mice treated with HFD + STZ were divided into four groups: diabetes control (HFD + STZ), P, LG, and P + LG, while the control group (NCD) was fed with the normal-chow diet. Significant amelioration was observed in the combination therapy as compared to monotherapies in respect of (i) insulin resistance, glucose intolerance, lipid profile, adiponectin levels, and mitochondrial complexes I, II, and III activities, (ii) reduced phosphoenolpyruvate carboxykinase, glucose 6-phophatase, glycogen phosphorylase, and GLUT2 transcript levels with increased glycogen content in the liver, (iii) restoration of insulin receptor 1ß, pAkt/Akt, and AdipoR1 protein levels in skeletal muscle, and (iv) significant increase in islet number due to ß-cell regeneration and reduced ß-cell death. L-glutamine and pitavastatin in combination can ameliorate T2D by inducing ß-cell regeneration and regulating glucose homeostasis.

Pleurisy secondary to nonthrombotic pulmonary emboli in a patient with intravenous drug use.

Patients with injection drug use can have nonthrombotic pulmonary emboli (NTPE) of foreign insoluble particles that are either parts of the equipment used or mixed with the drug as an additive. These foreign particles can become a nidus for infection and inflammation. We present a case of a 31-year-old man with active intravenous drug use who initially presented with signs and symptoms of pleurisy and was found to have NTPE of septic refractile crystalline material as seen on bronchial wash and brush biopsy. We believe our patient likely had embolism of either crack particles, needle fragments or cotton-wool fragments that led to a localized inflammatory reaction and infection. This highlights the importance of obtaining detailed history and diagnostic workup. Once the diagnoses of bacterial endocarditis and thrombophlebitis are ruled out with blood cultures, transthoracic echocardiogram, trans-esophageal echocardiogram and/or CT scan (depending on the suspicion), NTPE should be considered and bronchoscopy with bronchoalveolar lavage with biopsy should be performed.