Title: What Is a Choledochojejunostomy?
Category: Procedures and Tests
Created: 5/6/2020 12:00:00 AM
Last Editorial Review: 5/6/2020 12:00:00 AM

Title: How Long Does a Cholecystostomy Tube Stay In?
Category: Procedures and Tests
Created: 5/7/2020 12:00:00 AM
Last Editorial Review: 5/7/2020 12:00:00 AM

Title: What Is a Partial Gastrectomy?
Category: Procedures and Tests
Created: 5/7/2020 12:00:00 AM
Last Editorial Review: 5/7/2020 12:00:00 AM

Title: Got Flu? Deal Quickly With Complications
Category: Health News
Created: 2/2/2020 12:00:00 AM
Last Editorial Review: 2/3/2020 12:00:00 AM

Title: Were You Born in an H1N1 Flu Year or an H3N2? It Matters
Category: Health News
Created: 2/11/2020 12:00:00 AM
Last Editorial Review: 2/12/2020 12:00:00 AM

Title: Flu Season That's Sickened 26 Million May Be at Its Peak
Category: Health News
Created: 2/21/2020 12:00:00 AM
Last Editorial Review: 2/21/2020 12:00:00 AM

Title: azithromycin (Zithromax): Potential COVID-19 Combo Drug
Category: Medications
Created: 12/31/1997 12:00:00 AM
Last Editorial Review: 3/30/2020 12:00:00 AM

Title: Many Car Crash Deaths Involve Alcohol Levels Below Legal Limit: Study
Category: Health News
Created: 3/16/2020 12:00:00 AM
Last Editorial Review: 3/17/2020 12:00:00 AM

Title: The Doctor Gap: In Areas of Greatest Need, Primary Care Is a Team Effort
Category: Health News
Created: 3/19/2020 12:00:00 AM
Last Editorial Review: 3/20/2020 12:00:00 AM

Title: High Heat, Humidity Could Affect More Than 1.2 Billion People by End of Century
Category: Health News
Created: 3/24/2020 12:00:00 AM
Last Editorial Review: 3/25/2020 12:00:00 AM

Title: Women Are Much Safer Drivers Than Men, British Study Finds
Category: Health News
Created: 4/7/2020 12:00:00 AM
Last Editorial Review: 4/7/2020 12:00:00 AM

Title: Broiling in a Heat Wave? Wet T-shirt Can Safely Cool You Down
Category: Health News
Created: 4/13/2020 12:00:00 AM
Last Editorial Review: 4/14/2020 12:00:00 AM

Title: More Trees, Parks May Mean Longer Lives for City Dwellers
Category: Health News
Created: 4/28/2020 12:00:00 AM
Last Editorial Review: 4/29/2020 12:00:00 AM

Title: Replace That Old Carpet to Shield Your Kids From Toxins
Category: Health News
Created: 4/29/2020 12:00:00 AM
Last Editorial Review: 4/30/2020 12:00:00 AM

Title: When Booze Labels Carry Health Warnings, Drinking Declines: Study
Category: Health News
Created: 5/4/2020 12:00:00 AM
Last Editorial Review: 5/4/2020 12:00:00 AM

Title: Have a Hangover? Try This Herbal Remedy
Category: Health News
Created: 5/1/2020 12:00:00 AM
Last Editorial Review: 5/4/2020 12:00:00 AM

Title: Dangerously Hot Days for U.S. Farm Workers Could Double by 2050
Category: Health News
Created: 5/5/2020 12:00:00 AM
Last Editorial Review: 5/6/2020 12:00:00 AM

Title: AI May Help Guide Patients to Most Effective Antidepressant
Category: Health News
Created: 2/10/2020 12:00:00 AM
Last Editorial Review: 2/11/2020 12:00:00 AM

Title: Cymbalta (duloxetine)
Category: Medications
Created: 7/11/2007 12:00:00 AM
Last Editorial Review: 2/12/2020 12:00:00 AM

Title: Trazodone (Desyrel)
Category: Medications
Created: 3/26/1998 12:00:00 AM
Last Editorial Review: 2/12/2020 12:00:00 AM

Title: Teen Moms at High Risk for Depression, Anxiety
Category: Health News
Created: 2/28/2020 12:00:00 AM
Last Editorial Review: 3/2/2020 12:00:00 AM

Title: Is Electroconvulsive (ECT) Therapy Safe?
Category: Procedures and Tests
Created: 3/6/2020 12:00:00 AM
Last Editorial Review: 3/6/2020 12:00:00 AM

Title: Is the 'Gratitude Movement' Overrated? Study Finds It Has Limits
Category: Health News
Created: 3/16/2020 12:00:00 AM
Last Editorial Review: 3/17/2020 12:00:00 AM

Title: Tukysa Approved for Unresectable, Metastatic HER2-Positive Breast Cancer
Category: Health News
Created: 4/20/2020 12:00:00 AM
Last Editorial Review: 4/21/2020 12:00:00 AM

Title: Parent or Sibling With Colon Cancer? You May Need Colonoscopy Earlier
Category: Health News
Created: 4/20/2020 12:00:00 AM
Last Editorial Review: 4/21/2020 12:00:00 AM

Title: FDA Approves Trodelvy for Metastatic Triple-Negative Breast Cancer
Category: Health News
Created: 4/24/2020 12:00:00 AM
Last Editorial Review: 4/24/2020 12:00:00 AM

Title: Vyxeos (daunorubicin and cytarabine)
Category: Medications
Created: 4/24/2020 12:00:00 AM
Last Editorial Review: 4/24/2020 12:00:00 AM

Title: Kyprolis (carfilzomib)
Category: Medications
Created: 4/27/2020 12:00:00 AM
Last Editorial Review: 4/27/2020 12:00:00 AM

Title: Obamacare May Have Boosted Use of Mammograms
Category: Health News
Created: 5/1/2020 12:00:00 AM
Last Editorial Review: 5/4/2020 12:00:00 AM

Title: Traveling Abroad? Make Sure Your Measles Shot Is Up to Date
Category: Health News
Created: 7/24/2019 12:00:00 AM
Last Editorial Review: 7/24/2019 12:00:00 AM

Title: Typhoid Fever
Category: Diseases and Conditions
Created: 12/31/1997 12:00:00 AM
Last Editorial Review: 10/28/2019 12:00:00 AM

Title: Some Cities' Smog Can Ruin Your Vacation
Category: Health News
Created: 12/3/2019 12:00:00 AM
Last Editorial Review: 12/3/2019 12:00:00 AM

Title: U.S. Issues Highest Travel Alert for China as WHO Declares Health Emergency
Category: Health News
Created: 1/31/2020 12:00:00 AM
Last Editorial Review: 2/3/2020 12:00:00 AM

Title: How Safe Is It to Fly?
Category: Health News
Created: 2/24/2020 12:00:00 AM
Last Editorial Review: 2/25/2020 12:00:00 AM

Title: Untreated Sleep Apnea Puts Your Heart at High Risk
Category: Health News
Created: 2/3/2020 12:00:00 AM
Last Editorial Review: 2/4/2020 12:00:00 AM

Title: Silence Your Snore, Save Your Romance
Category: Health News
Created: 2/9/2020 12:00:00 AM
Last Editorial Review: 2/10/2020 12:00:00 AM

Title: Restful Romance: Smelling Your Lover's Shirt Can Help You Sleep
Category: Health News
Created: 2/14/2020 12:00:00 AM
Last Editorial Review: 2/14/2020 12:00:00 AM

Title: Erratic Sleep Habits May Boost Risk of Heart Problems: Study
Category: Health News
Created: 3/4/2020 12:00:00 AM
Last Editorial Review: 3/5/2020 12:00:00 AM

Title: Get Ready for Clocks to 'Spring Ahead'
Category: Health News
Created: 3/6/2020 12:00:00 AM
Last Editorial Review: 3/6/2020 12:00:00 AM

Title: A Consistent Bedtime Is Good for Your Heart
Category: Health News
Created: 4/3/2020 12:00:00 AM
Last Editorial Review: 4/6/2020 12:00:00 AM

Title: Using Pot to Help You Sleep? It Could Backfire
Category: Health News
Created: 4/14/2020 12:00:00 AM
Last Editorial Review: 4/15/2020 12:00:00 AM

Title: First Good Evidence That Brain Hits 'Replay' While You Sleep
Category: Health News
Created: 5/5/2020 12:00:00 AM
Last Editorial Review: 5/6/2020 12:00:00 AM

This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5–25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for MET amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, n = 15; dose expansion, n = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia (n = 9, 20.0%) and fatigue (n = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with MET-amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors (n = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with MET-amplified advanced solid tumors.

Long noncoding RNAs (lncRNA) have been found to play critical roles in tumorigenesis and the development of various cancers, including hepatocellular carcinoma (HCC). Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) has been identified as an oncogene and prognostic biomarker in HCC. Here, we demonstrated that MALAT1 expression was obviously high in sorafenib-resistant HCC cells. Furthermore, knockdown of MALAT1 increased sorafenib sensitivity in nonresponsive HCC cells, whereas forced expression of MALAT1 conferred sorafenib resistance to responsive HCC cells in vitro. In addition, loss/gain-of-function assays revealed that MALAT1 promoted cell proliferation, migration, and epithelial–mesenchymal transition in HCC cells. Mechanistically, MALAT1 regulated Aurora-A expression by sponging miR-140-5p, thus promoting sorafenib resistance in HCC cells. Moreover, MALAT1 inhibition enhanced the antitumor efficacy of sorafenib in vivo. Clinically, we found that MALAT1 expression was negatively correlated with miR-140-5p expression but positively correlated with Aurora-A expression in patients with HCC and that upregulated MALAT1 was closely correlated with poor survival outcomes in patients with HCC. These findings indicated that MALAT1 may be a novel target for prognosis prediction and therapeutic strategies in patients with HCC treated with sorafenib.

There is a need to develop novel approaches to improve the balance between efficacy and toxicity for transcription factor–targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach to improve the activity and limit the toxicity of the EWS-FLI1–targeted small molecule, mithramycin, for Ewing sarcoma. The clinical activity of mithramycin for Ewing sarcoma is limited by off-target liver toxicity that restricts the serum concentration to levels insufficient to inhibit EWS-FLI1. In this study, we perform an siRNA screen of the druggable genome followed by a matrix drug screen to identify mithramycin potentiators and a synergistic "class" effect with cyclin-dependent kinase 9 (CDK9) inhibitors. These CDK9 inhibitors enhanced the mithramycin-mediated suppression of the EWS-FLI1 transcriptional program leading to a shift in the IC₅₀ and striking regressions of Ewing sarcoma xenografts. To determine whether these compounds may also be liver protective, we performed a qPCR screen of all known liver toxicity genes in HepG2 cells to identify mithramycin-driven transcriptional changes that contribute to the liver toxicity. Mithramycin induces expression of the BTG2 gene in HepG2 but not Ewing sarcoma cells, which leads to a liver-specific accumulation of reactive oxygen species (ROS). siRNA silencing of BTG2 rescues the induction of ROS and the cytotoxicity of mithramycin in these cells. Furthermore, CDK9 inhibition blocked the induction of BTG2 to limit cytotoxicity in HepG2, but not Ewing sarcoma cells. These studies provide the basis for a synergistic and less toxic EWS-FLI1–targeted combination therapy for Ewing sarcoma.

Expression of the DNA/RNA helicase schlafen family member 11 (SLFN11) has been identified as a sensitizer of tumor cells to DNA-damaging agents including platinum chemotherapy. We assessed the impact of SLFN11 expression on response to platinum chemotherapy and outcomes in patients with metastatic castration-resistant prostate cancer (CRPC). Tumor expression of SLFN11 was assessed in 41 patients with CRPC treated with platinum chemotherapy by RNA sequencing (RNA-seq) of metastatic biopsy tissue (n = 27) and/or immunofluorescence in circulating tumor cells (CTC; n = 20). Cox regression and Kaplan–Meier methods were used to evaluate the association of SLFN11 expression with radiographic progression-free survival (rPFS) and overall survival (OS). Multivariate analysis included tumor histology (i.e., adenocarcinoma or neuroendocrine) and the presence or absence of DNA repair aberrations. Patient-derived organoids with SLFN11 expression and after knockout by CRISPR-Cas9 were treated with platinum and assessed for changes in dose response. Patients were treated with platinum combination (N = 38) or platinum monotherapy (N = 3). Median lines of prior therapy for CRPC was two. Median OS was 8.7 months. Overexpression of SLFN11 in metastatic tumors by RNA-seq was associated with longer rPFS compared with those without overexpression (6.9 vs. 2.8 months, HR = 3.72; 95% confidence interval (CI), 1.56–8.87; P < 0.001); similar results were observed for patients with SLFN11-positive versus SLFN11-negative CTCs (rPFS 6.0 vs. 2.2 months, HR = 4.02; 95% CI, 0.77–20.86; P = 0.002). A prostate-specific antigen (PSA) decline of ≥50% was observed in all patients with SLFN11 overexpression. No association was observed between SLFN11 expression and OS. On multivariable analysis, SLFN11 was an independent factor associated with rPFS on platinum therapy. Platinum response of organoids expressing SLFN11 was reduced after SLFN11 knockout. Our data suggest that SLFN11 expression might identify patients with CRPC with a better response to platinum chemotherapy independent of histology or other genomic alterations. Additional studies, also in the context of PARP inhibitors, are warranted.

KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a double-stranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150–180 mg/m²) and pelareorep (1 x 10¹⁰ TCID₅₀–3 x 10¹⁰ TCID₅₀)] was implemented in adult patients with oxaliplatin refractory/intolerant, KRAS-mutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1–5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-naïve patients, the highest dose of FOLFIRI/bevacizumab (180 mg/m² irinotecan) and pelareorep (3 x 10¹⁰ TCID₅₀) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid -1 protein demonstrated viral "homing" in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of pelareorep with FOLFIRI/bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.

TNF-related apoptosis-inducing ligand (TRAIL) and an agonistic antibody against the death-inducing TRAIL receptor 5, DR5, are thought to selectively induce tumor cell death and therefore, have gained attention as potential therapeutics currently under investigation in several clinical trials. However, some tumor cells are resistant to TRAIL/DR5–induced cell death, even though they express DR5. Previously, we reported that DR5 is transported into the nucleus by importin β1, and knockdown of importin β1 upregulates cell surface expression of DR5 resulting in increased TRAIL sensitivity in vitro. Here, we examined the impact of importin β1 knockdown on agonistic anti-human DR5 (hDR5) antibody therapy. Drug-inducible importin β1 knockdown sensitizes HeLa cells to TRAIL-induced cell death in vitro, and exerts an antitumor effect when combined with agonistic anti-hDR5 antibody administration in vivo. Therapeutic importin β1 knockdown, administered via the atelocollagen delivery system, as well as treatment with the importin β inhibitor, importazole, induced regression and/or eradication of two human TRAIL-resistant tumor cells when combined with agonistic anti-hDR5 antibody treatment. Thus, these findings suggest that the inhibition of importin β1 would be useful to improve the therapeutic effects of agonistic anti-hDR5 antibody against TRAIL-resistant cancers.

Dysregulation of DNA methylation is an established feature of breast cancers. DNA demethylating therapies like decitabine are proposed for the treatment of triple-negative breast cancers (TNBC) and indicators of response need to be identified. For this purpose, we characterized the effects of decitabine in a panel of 10 breast cancer cell lines and observed a range of sensitivity to decitabine that was not subtype specific. Knockdown of potential key effectors demonstrated the requirement of deoxycytidine kinase (DCK) for decitabine response in breast cancer cells. In treatment-naïve breast tumors, DCK was higher in TNBCs, and DCK levels were sustained or increased post chemotherapy treatment. This suggests that limited DCK levels will not be a barrier to response in patients with TNBC treated with decitabine as a second-line treatment or in a clinical trial. Methylome analysis revealed that genome-wide, region-specific, tumor suppressor gene–specific methylation, and decitabine-induced demethylation did not predict response to decitabine. Gene set enrichment analysis of transcriptome data demonstrated that decitabine induced genes within apoptosis, cell cycle, stress, and immune pathways. Induced genes included those characterized by the viral mimicry response; however, knockdown of key effectors of the pathway did not affect decitabine sensitivity suggesting that breast cancer growth suppression by decitabine is independent of viral mimicry. Finally, taxol-resistant breast cancer cells expressing high levels of multidrug resistance transporter ABCB1 remained sensitive to decitabine, suggesting that the drug could be used as second-line treatment for chemoresistant patients.

2-fluorofucose (2FF) inhibits protein and cellular fucosylation. Afucosylation of IgG antibodies enhances antibody-dependent cell-mediated cytotoxicity by modulating antibody affinity for FcRIIIa, which can impact secondary T-cell activation. Immune responses toward most common solid tumors are dominated by a humoral immune response rather than the presence of tumor-infiltrating cytotoxic T cells. IgG antibodies directed against numerous tumor-associated proteins are found in the sera of both patients with breast cancer and transgenic mice bearing mammary cancer. We questioned whether 2FF would have antitumor activity in two genetically distinct transgenic models; TgMMTV-neu (luminal B) and C3(1)-Tag (basal) mammary cancer. 2FF treatment significantly improved overall survival. The TgMMTV-neu doubled survival time compared with controls [P < 0.0001; HR, 7.04; 95% confidence interval (CI), 3.31–15.0], and survival was significantly improved in C3(1)-Tag (P = 0.0013; HR, 3.36; 95% CI, 1.58–7.14). 2FF treated mice, not controls, developed delayed-type hypersensitivity and T-cell responses specific for syngeneic tumor lysates (P < 0.0001). Serum IgG from 2FF-treated mice enhanced tumor lysis more efficiently than control sera (P = 0.004). Administration of 2FF for prophylaxis, at two different doses, significantly delayed tumor onset in both TgMMTV-neu; 20 mmol/L (P = 0.0004; HR, 3.55; 95% CI, 1.60–7.88) and 50 mmol/L (P = 0.0002; HR: 3.89; 95% CI, 1.71–8.86) and C3(1)-Tag; 20 mmol/L (P = 0.0020; HR, 2.51; 95% CI, 1.22–5.18), and 50 mmol/L (P = 0.0012; HR, 3.36; 95% CI, 1.57–7.18). Mammary cancer was prevented in 33% of TgMMTV-neu and 26% of C3(1)-Tag. 2FF has potent antitumor effects in mammary cancer models. The agent shows preclinical efficacy for both cancer treatment and prevention.