Therapeutic effiacy of T cells expressing chimeric antigen receptor derived from a mesothelin-specific scFv in orthotopic human pancreatic cancer animal models

Novel CAR T cells targeting mesothelin (MSLN) expressed on pancreatic cancer cells were developed to overcome the limit of the clinical efficacy of CAR T cell therapy for pancreatic cancer patients. Optimal single-chain variable fragments (scFv) binding to MSLN were selected based on the binding activity and the functional effectiveness of various scFv containing CAR-expressing T cells. Engineered MSLN CAR T cells showed successful anti-tumor activity specific to MSLN expression level. Furthermore, MSLN CAR T cells were evaluated for the anti-cancer efficacy in orthotopic mouse models bearing pancreatic cancer cells, MIA Paca-2, MSLN-overexpressed MIA Paca-2 or endogenously MSLN-expressing AsPC-1. Mice were randomized into control, mock treated, MS501 BBz treated, MS501 28z treated or MS501 28BBz treated group. Mice were monitored by weekly IVIS imaging and tumors were harvested and analyzed by immunohistochemical analyses. MSLN CAR T cells produced the therapeutic effect in orthotopic animal models with complete remission in significant number of mice. Histopathological analysis indicated that CD4+ and CD8+ MSLN CAR T cells infiltrated pancreatic tumor tissue and led to cancer cell eradication. Our results demonstrated the anti-tumor efficacy of MSLN CAR T cell therapy against pancreatic cancer, suggesting its therapeutic potential.     

A Case of Mucosal Fixed Drug Eruption Caused by Tamsulosin Administration

Fixed drug eruption (FDE) is a rare type of drug reaction that involves the skin and, less commonly, the mucosal membranes. It is characterized by clinically well-defined erythematous patches or plaques with or without blisters, which relapse at the same location if the causative agent is readministered. Tamsulosin is an alpha-1 adrenergic receptor blocker used to treat benign prostatic hyperplasia, and its common side effects are dizziness and headache. Only one case of cutaneous FDE due to tamsulosin administration has been reported but no other case of mucosal involvement has been reported to date. Therefore, we present a case of mucosal FDE caused by tamsulosin administration along with a literature review.     

Molecular Basis of Resveratrol-Induced Resensitization of Acquired Drug-Resistant Cancer Cells

Multidrug resistance (MDR) to anticancer drugs remains a serious obstacle to the success of cancer chemotherapy. Resveratrol, a polyphenol, present in natural products exerts anticancer activity and acts as a potential MDR inhibitor in various drug-resistant cancer cells. In the process of resensitization of drug-resistant cancer cells, resveratrol has been shown to interfere with ABC transporters and drug-metabolizing enzymes, increase DNA damage, inhibit cell cycle progression, and induce apoptosis and autophagy, as well as prevent the induction of epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). This review summarizes the mechanisms by which resveratrol counteracts MDR in acquired drug-resistant cancer cell lines and provides a critical basis for understanding the regulation of MDR as well as the development of MDR-inhibiting drugs.     

Simple Nutrient-Based Rules vs. a Nutritionally Rich Plant-Centered Diet in Prediction of Future Coronary Heart Disease and Stroke: Prospective Observational Study in the US

To better understand nutrition paradigm shift from nutrients to foods and dietary patterns, we compared associations of a nutrient-based blood cholesterol-lowering diet vs. a food-based plant-centered diet with risk of coronary heart disease (CHD) and stroke. Participants were 4701 adults aged 18–30 years and free of cardiovascular disease at baseline, followed for clinical events from 1985 and 86 to 2018. A plant-centered diet was represented by higher A Priori Diet Quality Score (APDQS). A blood cholesterol-lowering diet was represented by lower Keys Score. Proportional hazards regression was used to calculate hazard ratios (HR). Higher APDQS showed a nutrient-dense composition that is low in saturated fat but high in fiber, vitamins and minerals. Keys Score and APDQS changes were each inversely associated with concurrent plasma low-density lipoprotein cholesterol (LDL-C) change. Over follow-up, 116 CHD and 80 stroke events occurred. LDL-C predicted CHD, but not stroke. APDQS, but not Keys Score, predicted lower risk of CHD and of stroke. Adjusted HRs (95% CIs) for each 1-SD higher APDQS were 0.73 (0.55–0.96) for CHD and 0.70 (0.50–0.99) for stroke. Neither low dietary fat nor low dietary carbohydrate predicted these events. Our findings support the ongoing shift in diet messages for cardiovascular prevention.     

Efficacy and Safety of Pregabalin for Muscle Cramps in Liver Cirrhosis: A Double-Blind Randomized Controlled Trial

BackgroundMuscle cramp is possibly related to peripheral nerve hyperexcitability (PNH), and one of the most debilitating symptoms frequently encountered in patients with liver cirrhosis. We investigated whether pregabalin, a gamma-aminobutyric acid analogue, can suppress neuronal excitability and reduce muscle cramps in cirrhotic patients.MethodsWe conducted a randomized, double-blind, placebo-controlled trial in which study participants with cirrhosis from a single tertiary center were enrolled. Primary endpoint was the relative change in cramp frequency from the run-in to standard dose treatment phase (4 weeks per each). Secondary endpoints included the responder rate, and the changes in cramp frequency during sleep, pain intensity, health-related quality of life (Liver Disease Quality of Life Instrument, Short Form-36) and electrophysiological measures of PNH.ResultsThis study was terminated early because of insufficient accrual. 80% (n = 56) of the target number of participants (n = 70) were randomized to pregabalin (n = 29) or placebo (n = 27). Median baseline frequency of muscle cramps (interquartile range) was 5.8 (3.5–10) per week in the pregabalin group and 6.5 (4.0–10) in the placebo group (P = 0.970). The primary analysis showed a significant reduction in cramp frequency with pregabalin compared to placebo (−36% vs. 4.5% for the percentage change, P = 0.010). Secondary outcomes did not differ significantly between the two groups. Adverse effects with pregabalin were mainly dizziness and lethargy.ConclusionWith multiple problems emerging from premature termination in mind, the results suggested an acceptable safety profile and favorable effect of pregabalin in reducing muscle cramps compared to placebo in cirrhotic patients.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01271660","term_id":"NCT01271660"}}NCT01271660     

Sodium-Glucose Cotransporter-2 Inhibitor-Related Diabetic Ketoacidosis: Accuracy Verification of Operational Definition

BackgroundThe most important aspect of a retrospective cohort study is the operational definition (OP) of the disease. We developed a detailed OP for the detection of sodium-glucose cotransporter-2 inhibitors (SGLT2i) related to diabetic ketoacidosis (DKA). The OP was systemically verified and analyzed.MethodsAll patients prescribed SGLT2i at four university hospitals were enrolled in this experiment. A DKA diagnostic algorithm was created and distributed to each hospital; subsequently, the number of SGLT2i-related DKAs was confirmed. Then, the algorithm functionality was verified through manual chart reviews by an endocrinologist using the same OP.ResultsA total of 8,958 patients were initially prescribed SGLT2i. According to the algorithm, 0.18% (16/8,958) were confirmed to have SGLT2i-related DKA. However, based on manual chart reviews of these 16 cases, there was only one case of SGLT2i-related DKA (positive predictive value = 6.3%). Even after repeatedly narrowing the diagnosis range of the algorithm, the effect of a positive predictive value was insignificant (6.3–10.0%, P > 0.999).ConclusionOwing to the nature of electronic medical record data, we could not create an algorithm that clearly differentiates SGLT2i-related DKA despite repeated attempts. In all retrospective studies, a portion of the samples should be randomly selected to confirm the accuracy of the OP through chart review. In retrospective cohort studies in which chart review is not possible, it will be difficult to guarantee the reliability of the results.     

A case of cutaneous extranodal natural killer/T-cell lymphoma clinically and histopathologically mimicking interface dermatitis

Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare but aggressive cancer characterised by angiocentric and angiodestructive infiltration by NK-cells, or cytotoxic T-cell types. Histopathologically, ENKTL shows a multinodular or diffuse infiltration localised to vascular structures, resulting in angiodestruction and necrosis. We present a patient with an initially suspected diagnosis of benign interface dermatitis with a differential diagnosis of mycosis fungoides that was later found to be an aggressive extranodal natural killer/T-cell lymphoma of a nasal type and with a dismal prognosis.     

Necrobiotic Xanthogranuloma Coexists with Diffuse Normolipidemic Plane Xanthoma and Multiple Myeloma

Necrobiotic xanthogranuloma (NXG), is a rare multisystem disease that manifests as cutaneous inflammatory lesions, and is commonly associated with lymphoproliferative disease. Diffuse normolipemic plane xanthoma (NX), is also a rare, acquired disease that is often associated with systemic diseases such as lymphoproliferative disease. Both of these diseases have been reported to be associated with monoclonal gammopathy (MG). However, there are few cases in which these diseases co-exist. A 78-year-old female, who had a known case of NX on the neck and axillary area, presented with an asymptomatic erythematous plaque on her left supraclavicular area. Histopathological examination showed lymphoid aggregates, necrobiotic areas, and granulomatous inflammation in the dermis. Numerous foreignbody and Touton type giant cells were noticed. Serum protein immunoelectrophoresis showed an IgG kappa type MG. Lipid profile of the patient was normal. Bone marrow examination showed plasma cell myeloma. Based on these histologic and laboratory results, we diagnosed this lesion as NXG coexisting with NX and multiple myeloma. She was started on treatment with bortezomib and melphalan for multiple myeloma, and high-dose systemic corticosteroid and triamcinolone intralesional injection for the skin lesion. After 3 months of treatment, the NXG skin lesion and MG improved.