In light of the burgeoning successes of cancer immunotherapy, glioblastoma (GBM) remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity. Thus, identifying promising therapeutic targets for treating GBM and discovering methodologies to effectively regulate them is still a tremendous challenge. Here we describe photodynamic protein tyrosine phosphatase 1B (PTP1B) proteolysis mediated by a proteolysis-targeting chimera (PROTAC) nanoassembly. The PTP1B-targeting PROTAC is conjugated with a photosensitizer via a cathepsin B (Cat B)-cleavable peptide, which spontaneously forms nanoassemblies due to intermolecular π-π stacking interactions. In GBM models, PROTAC nanoassemblies significantly accumulate in the tumor region across the disrupted blood-brain barrier (BBB), triggering a burst release of the photosensitizer and active PROTAC by Cat B-mediated enzymatic cleavage. Upon laser irradiation, photodynamic therapy (PDT) synergizes with PROTAC-mediated PTP1B proteolysis to induce potent immunogenic cell death (ICD) in tumor cells. Subsequently, persistent PTP1B degradation by nanoassemblies in Cat B-overexpressed intratumoral T cells downregulates exhaustion markers, reinvigorating their functionality. These sequential processes of photodynamic PTP1B proteolysis ultimately augment T cell-mediated antitumor immunity as well as protective immunity, completely eradicating the primary GBM and preventing its recurrence. Overall, our findings underscore the therapeutic potential of combining PDT with PROTAC activity for GBM immunotherapy.

It has been reported that ingestion of raw or undercooked shiitake mushrooms is associated with various adverse food reactions. A 58-year-old man presented with pruritic and maculopapular rashes on the trunk and extremities starting 1 day after ingestion of partially uncooked shiitake mushrooms. A probable diagnosis of systemic allergic contact dermatitis was made. Raw and cooked shiitake mushroom-derived allergen extracts were prepared, and patch and intradermal tests with delayed readings were performed. The case showed positive intradermal test results with delayed readings to the raw, but not cooked, extracts. The case suggests that ingestion of uncooked shiitake mushrooms may induce systemic allergic contact dermatitis through type IV hypersensitivity reaction.
Dermatitis, Allergic Contact* ; Dermatitis, Contact ; Diagnosis ; Eating ; Exanthema ; Extremities ; Humans ; Hypersensitivity, Delayed ; Intradermal Tests ; Middle Aged ; Patch Tests ; Reading ; Shiitake Mushrooms

This paper aims to introduce, summarize, and emphasize the importance of the 'Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition'. The guideline broadly covers most aspects of the pharmacological treatment of patients in Korea diagnosed with moderate to severe major depression according to the DSM-IV TR. The guideline establishment process involved determining and answering a number of key questions, searching and selecting publications, evaluating recommendations, preparing guideline drafts, undergoing external expert reviews, and obtaining approval. A guideline adaptation process was conducted for the revised edition. The guideline strongly recommends pharmacological treatment considered appropriate to the current clinical situation in Korea, and should be considered helpful when selecting the appropriate pharmacological treatment of patients diagnosed with major depressive disorder. Therefore, the wide distribution of this guideline is recommended.
Antidepressive Agents/*therapeutic use ; Antipsychotic Agents/therapeutic use ; Databases, Factual ; Depression/complications/diagnosis/*drug therapy ; Drug Tolerance ; Evidence-Based Practice ; Humans ; Monoamine Oxidase Inhibitors/therapeutic use ; Neurotransmitter Uptake Inhibitors/therapeutic use ; Placebo Effect ; Psychotic Disorders/complications/drug therapy ; Republic of Korea ; Severity of Illness Index

OBJECTIVES: The aim of this study is to establish Korean pharmacological treatment guidelines for the initial choice of antidepressant for treatment of moderate or severe depression. METHODS: The process for establishment of guidelines involved determination of important key questions, selection of 12 international and domestic clinical practice guidelines for depression, drawing of recommendation drafts, and peer review. RESULTS: Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors (NDRI), and noradrenergic and specific serotonergic antidepressants (NaSSA) were strongly recommended as the first-line antidepressants for treatment of moderate or severe depression. SSRIs were weakly recommended for patients who had problems with tolerability. Consideration of not only efficacy but also provisional adverse effects, drug-drug interactions, history of treatment response, preference, acceptability, cost, comorbid illnesses, and other factors in the choice of first-line antidepressants was strongly recommended. The treatment recommendations for specific clinical features of depression were as follows. SSRIs were weakly recommended for atypical depression. Augmented use of antipsychotics to antidepressants was strongly recommended for psychotic depression. Bupropion and SSRIs were weakly recommended for seasonal depression. CONCLUSION: The results of this study may contribute toward improving the quality of depression treatment by providing clear and definite recommendations for the initial choice of antidepressant for treatment of moderate or severe depression.
Antidepressive Agents ; Antipsychotic Agents ; Bupropion ; Depression ; Humans ; Seasons ; Serotonin Uptake Inhibitors

OBJECTIVES: The aim of this study was to demonstrate the recommendations for antidepressant treatment strategy of dose increment, switching, combination, and augmentation therapy derived from Evidence-Based Korean Pharmacological Treatment Guideline for Depression, Revised Edition. METHODS: The guideline was developed through adaptation of 12 domestic and foreign clinical guidelines for depression, with key questions concerning pharmacotherapy of depression, and drawing of recommendations. RESULTS: The guideline strongly recommended dose increment, switching, and combination and augmentation therapy of antidepressant when patients with depression showed inadequate treatment outcomes from initial antidepressant treatment. The dose increment was strongly recommended when the patients had insufficient response from treatment with tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), and serotonin and norepinephrine reuptake inhibitors (SNRIs). Switching from SSRI to non-SSRI was also strongly recommended. The combination of initial medication and other classes of antidepressants could benefit from treatment with TCAs, SSRIs, SNRIs, and noradrenergic and specific serotonergic antidepressants. Combination with norepinephrine and dopamine reuptake inhibitors or serotonin-2 antagonist/reuptake inhibitors was weakly recommended. The guideline strongly recommended use of the augmentation strategy of adding lithium or benzodiazepine to initial antidepressants. Augmentation of lamotrigine, T3, methylphenidate, and modafinil was weakly recommended. CONCLUSION: If the initial outcomes of antidepressant therapy are unsatisfactory to the patients the next-step strategies of dose increment, switching, combination and augmentation of antidepressants should be considered after rechecking the patients' drug compliance, dose, and diagnosis.
Antidepressive Agents ; Antidepressive Agents, Tricyclic ; Benzhydryl Compounds ; Benzodiazepines ; Compliance ; Depression* ; Depressive Disorder, Major ; Dopamine Uptake Inhibitors ; Drug Therapy ; Humans ; Lithium ; Methylphenidate ; Monoamine Oxidase Inhibitors ; Norepinephrine ; Serotonin ; Serotonin Uptake Inhibitors ; Triazines

OBJECTIVES: The purpose of this study was to suggest recommendations of antidepressant efficacy compared with placebo, difference in efficacy of antidepressants, and appropriate time of efficacy judgment in antidepressant therapy. METHODS: Using recommendations from 12 international and domestic clinical practice guidelines for depression, drawing of recommendation drafts, and peer review, the executive committee developed the guideline. RESULTS: Tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOI), selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and specific serotonergic antidepressants (NaSSAs), norepinephrine and dopamine reuptake inhibitors (NDRIs), and serotonin antagonist and reuptake inhibitors (SARIs) were strongly recommended as having antidepressant efficacy compared with placebo. Difference in efficacy of antidepressants was as follows. TCAs, MAOI, SSRI, SNRIs, and NaSSAs were strongly recommended, however, NDRIs, SARIs were weakly recommended. If there was no or minimal improvement with treatment, appropriate time of efficacy judgment in antidepressant therapy was estimated to be after two to four weeks. CONCLUSION: We hope that the results of this study will be helpful in encouraging the optimal treatment by understanding antidepressant efficacy compared with placebo, difference in efficacy of antidepressants, and appropriate time of efficacy judgment in antidepressant therapy.
Antidepressive Agents* ; Antidepressive Agents, Tricyclic ; Depression* ; Depressive Disorder, Major ; Dopamine Uptake Inhibitors ; Judgment* ; Monoamine Oxidase Inhibitors ; Norepinephrine ; Peer Review ; Serotonin ; Serotonin Uptake Inhibitors

OBJECTIVE: Juvenile rheumatoid arthritis (JRA) may occur in the wake of infection with several viruses including Ebstein-barr virus (EBV). EBV remains an interesting target. To determine the possible role of EBV infections in the clinical course of JRA, we attempt to demonstrate the radiologic changes and the frequency prescription of etanercept rather than classic therapy. METHODS: Total of 87 patients with JRA, who were hospitalized in Hangang Sacred Hospital and Kangnam Sacred Hospital in Seoul from 2002 to 2010, were assessed serologically for EBV infection (anti EBV VCA IgM and IgG) at admission. Patients with JRA were devided 2 groups, one is EBV VCA IgG (+) JRA patients who had been infected before and another is EBV VCA IgG (-) JRA patients who had not. RESULTS: EBV VCA IgG (+) were seen in 55 patients (63.2%). 31 boys (76%) and 24 girls (52%) were infected with EBV. The mean age of patients of EBV (+) JRA was 8.2+/-3.6 years and that of EBV (-) JRA was 5.3+/-3.4 years. 7 of EBV (+) JRA (13%) developed radiologic change within 2 years, compare with none of EBV (-) JRA. 22 of EBV (+) JRA (49%) with JRA did not respond to the classic therapy, compare with 7 of EBV (-) JRA (22%). CONCLUSION: JRA patients with past EBV infection were older in ages, more in male, more radiologic changes, needed more biologic treatment than those without past EBV infection.
Arthritis, Juvenile Rheumatoid ; Child ; Epstein-Barr Virus Infections ; Herpesvirus 4, Human ; Humans ; Immunoglobulin G ; Immunoglobulin M ; Male ; Prescriptions ; Receptors, Tumor Necrosis Factor ; Viruses ; Etanercept

We investigated the immune response induced by the Francisella (F.) tularensis live vaccine strain (LVS) and the Pohang isolate. After the Balb/c mice were infected intradermally (i.d) with 2 x 10(4) cfu of F. tularensis LVS and Pohang, respectively, their blood and organs were collected at different times; 0, 3, 6, 24, 72, 96, 120 and 168 h after infection. Using these samples, RT-PCR and ELISA analysis were carried out for the comparative study of the cytokines, including TNF-alpha, INF-gamma, IL-2, IL-4, IL-10 and IL-12. In the Pohang-infected mice at 120 h, the liver showed a 53 times higher level of TNF-alpha and a 42 times higher level of IFN-gamma than the respective levels at the early time points after infection. The levels of TNF-alpha and IFN-gamma induced by LVS were 5 times lower than those induced by the Pohang isolate. Also, the organs from the Pohang-infected mice showed higher levels of TNF-alpha, IFN-gamma, IL-10 and IL-12 than the levels in the LVS-infected mice. The blood from the Pohang-infected mice at 120 h revealed about a 40 times increased level of IFN-gamma, and IL-10 was also increased by 4 times at 96 h compared to an early infection time point, while IL-4 was not induced during the whole infection period. These results suggest that F. tularensis may induce a Th1-mediated immune response to in vivo infection and the Pohang isolate has a higher capacity than the LVS to induce an acute immune response in Blab/c mice.
Animals ; *Bacterial Vaccines ; Cytokines/*biosynthesis ; Francisella tularensis/immunology/isolation & purification/*pathogenicity ; Humans ; Interferon-gamma/genetics/metabolism ; Interleukins/genetics/metabolism ; Korea ; Liver/microbiology/pathology ; Mice ; Mice, Inbred BALB C ; Polymerase Chain Reaction ; Tularemia/*diagnosis/*immunology ; Tumor Necrosis Factor-alpha/genetics/metabolism

BACKGROUND: Endogenous nitric oxide (NO) induces the peripheral vasodilation via the activation of guanylate cyclase in patients with septic shock. The purpose of this study was to assess the acute effects of methylene blue (MB), which is an inhibitor of guanylate cyclase, on the hemodynamics and on the production of pro-inflammatory cytokines and nitric oxide (NO) in patients with refractory septic shock. METHODS: Twenty consecutive patients with refractory septic shock, which was defined as shock refractory to a dopamine infusion of more than 20 microgram/kg/min with the appropriate use of antibiotics and adequate volume replacement, received MB infusion of 1 mg/kg intravenously. The hemodynamic and respiratory variables were measured at baseline, 30, 60 and 120 min after an infusion of MB (1 mg/kg). The blood levels of NO, IL-1, IL-10 and TNF-alpha were measured at baseline, 30 and 120 min after MB infusion. RESULTS: The administration of MB induced an increase in the systemic vascular resistance (SVR) that resulted in an increase of the mean arterial pressure (MAP) in patients with refractory septic shock, and this was without a decrease in cardiac output. The administered MB induced an increase in pulmonary vascular resistance (PVR) that resulted in an increase of pulmonary arterial pressure (PAP), without any deterioration of gas exchange. However, the increases in SVR and PVR were not associated with the alteration of endogenous production of NO, IL-1, IL-10 and TNF-alpha. CONCLUSION: MB transiently elevated the MAP by increasing the SVR without altering the endogenous productions of NO, IL-1, IL-10 and TNF-alpha during the study period in patients with refractory septic shock.
Anti-Infective Agents, Urinary/administration & dosage/*therapeutic use ; Blood Pressure/*drug effects/physiology ; Comparative Study ; Cytokines/*blood ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Infusions, Intravenous ; Male ; Methylene Blue/administration & dosage/*therapeutic use ; Middle Aged ; Pulmonary Circulation/drug effects/physiology ; Research Support, Non-U.S. Gov't ; Retrospective Studies ; Shock, Septic/blood/*drug therapy/physiopathology ; Treatment Outcome ; Vascular Resistance/*drug effects/physiology

BACKGROUND: This study compared the bronchodilator efficacy and safety of tiotropium inhalation capsules (18microgram once daily) with a ipratropium metered dose inhaler (2 puffs of 20microgram q.i.d.) in patients with chronic obstructive pulmonary disease (COPD). METHOD: After the initial screening assessment and a two-week run-in period, patients received either tiotropium 18microgram once daily or ipratropium 40microgram four times daily over a period of 4 weeks in a double blind, double dummy, parallel group study. The outcome measures were the lung function, the daily records of the peak expiratory flow rate (PEFR), the patients' questionnaire, and the use of concomitant salbutamol. The forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC) were measured 5 minutes before inhalation, and 0.5, 1, 2 and 3 hours after inhaling the study drug on days 0, 14 and 28. RESULT: In 16 centers, 134 patients with a mean (SD) age of 66 (7) years and a predicted FEV1 of 42 (12)% were analyzed. The trough FEV1 response was significantly higher in the tiotropium group than in the ipratropium group after a four-week treatment period. The weekly mean morning PEFR of the tiotropium group was consistently higher than that of the ipratropium group during the 4-week treatment period with differences ranging from 12.52 to 13.88 l/min, which were statistically significant. Tiotropium was well tolerated by the COPD patients during the 4-week treatment period and had a similar safety profile to ipratropium. CONCLUSION: This study shows that tiotropium administrated once daily has a superior bronchodilator effect with a similar safety profile in treating COPD patients compared with ipratropium, inhaled four times daily.
Adult* ; Albuterol ; Bronchodilator Agents ; Capsules ; Forced Expiratory Volume ; Humans ; Inhalation ; Ipratropium* ; Lung ; Mass Screening ; Metered Dose Inhalers ; Outcome Assessment (Health Care) ; Peak Expiratory Flow Rate ; Pulmonary Disease, Chronic Obstructive* ; Surveys and Questionnaires ; Vital Capacity ; Tiotropium Bromide