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KRAS mutations occur in a quarter of all human cancers. When activated in its GTP-bound form, RAS stimulates diverse cellular systems, such as cell division, differentiation, growth, and apoptosis through the activations of various signaling pathways, which include mitogen-activated protein kinase (MAPK), phosphoinositide 3 kinases (PI3K), and RAL-GEFs pathways. We found that GJ101 (

Posterior communicating artery aneurysms (PcomAAs) are the second most common type of aneurysm. Large cerebral aneurysms show various neurological symptoms, especially oculomotor nerve palsy (ONP), due to PcomAAs. Recent research has shown that stent-assisted coil embolization has many side effects. We report the effectiveness of Korean medicine in the treatment of ONP due to PcomAAs after stent-assisted coil embolization. A patient with ptosis and limitation of eye movement was treated with Korean medicine, including herbal medicine (Samlyeongbaegchul-san-byeonbang [參苓白朮散變方] and Uwhangchungsim-won [牛黃淸心元]), acupuncture, electroacupuncture, cupping, and moxibustion. Clinical symptoms were observed by images of the inter-palpebral fissure and eyeball movement. After the treatment, the inter-palpebral fissure and eyeball movement were noticeably improved. These findings suggest that treatment with Korean medicine can be an effective option for the treatment of ONP due to PcomAAs after stent-assisted coil embolization.

Background: We present a case of asthma-chronic obstructive pulmonary disease syndrome (ACOS), which has features of both asthma and chronic obstructive pulmonary disease, in a 63-year-old man treated with Korean medicine.Methods: For four weeks of hospitalization, the patient received acupuncture, Guarujisil-tang decoction, and herbal steam therapy. The main symptoms of ACOS, which are dyspnea, chest discomfort, and throat discomfort, were treated with acupuncture. Guarujisil-tang decoction and herbal steam therapy were administered to relieve cough and smooth the expectoration of mucus.Results: By the end of hospitalization, no significant change was observed in lung function. However, the patient's subjective symptoms, including dyspnea, chest discomfort, sore throat, and sweating, were improved. The patient's objective sign of opaque yellow mucus changed to clear mucus after the treatment. His scores for the quality of life questionnaire for adult Korean asthmatics and the modified Borg scale also showed improvement from 42 to 62 and from 3 to 1, respectively.Conclusions: Although we reported only one ACOS case, this study is significant in that case reports of ACOS treated with Korean medicine are rare. Further study is needed to confirm the effectiveness of Korean medicine in patients with ACOS.

Purpose: The purpose of this study is to report the improvement of tracheal granuloma after herbal medicine treatment.Methods: A patient with tracheal granuloma was treated with Sipyukmiyuki-eum, and we checked laryngoscopy images to observe the improvement of this condition.Results: After treatment with Sipyukmiyuki-eum and Korean medicine therapy, we found that tracheal granuloma showed improvements in the laryngoscopy image.Conclusion: This case suggests that Sipyukmiyuki-eum might be effective for patients who develop tracheal granuloma after tracheostomy. However, additional studies with more patients are required to verify this finding.

Purpose: The purpose of this paper is to report the improvement of a patient with amyotrophic lateral sclerosis after long-term combined Korean medical treatment.Methods: A patient diagnosed with amyotrophic lateral sclerosis was treated with herbal medicine, acupuncture, pharmacopuncture, moxibustion, and rehabilitation for four separate hospital stays. To evaluate their respiratory discomfort and limb weakness, we used Manual Muscle Testing, the Pulmonary Function Test, and the Korean Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised.Results: The weakness of the muscles of the lower extremities and respiratory function was improved.Conclusion: We consider that combined Korean medicine treatments might be an effective treatment for muscle weakness and respiratory discomfort of amyotrophic lateral sclerosis. To verify the effectiveness of these treatments, further research is required.

Objectives: The purpose of this study was to report the effectiveness of Korean medicine in the treatment of persistent postural-perceptual dizziness.Methods: A patient with dizziness was treated with Banhabackchulchunma-tang and Gongjin-dan herbal medicines. The severity of symptoms was assessed with a daily visual analog scale (VAS) for dizziness and the frequency of subjective trembling feelings (over 30 minutes).Results: After the treatment, the severity of dizziness was reduced from VAS 5 to VAS 2, and fatigue was improved from VAS 5 to VAS 1. The frequency of subjective trembling feelings was reduced from once every 3-4 days to once every 10 days. Other symptoms, such as dyspepsia, sleep disturbance, and hot flashes, also showed improvement.Conclusion: Treatment with Korean medicine may be an effective option for the treatment of persistent postural-perceptual dizziness.

Fas-associated death domain (FADD) is an adapter molecule that bridges the interaction between receptor-interacting protein 1 (RIP1) and aspartate-specific cysteine protease-8 (caspase-8). As the primary mediator of apoptotic cell death, caspase-8 has two N-terminal death-effector domains (DEDs) and it interacts with other proteins in the DED subfamily through several conserved residues. In the tumor necrosis receptor-1 (TNFR-1)-dependent signaling pathway, apoptosis is triggered by the caspase-8/FADD complex by stimulating receptor internalization. However, the molecular mechanism of complex formation by the DED proteins remains poorly understood. Here, we found that direct DED-DED interaction between FADD and caspase-8 and the structure-based mutations (Y8D/I128A, E12A/I128A, E12R/I128A, K39A/I128A, K39D/I128A, F122A/I128A, and L123A/I128A) of caspase-8 disrupted formation of the stable DED complex with FADD. Moreover, the monomeric crystal structure of the caspase-8 DEDs (F122A/I128A) was solved at 1.7 Å. This study will provide new insight into the interaction mechanism and structural characteristics between FADD and caspase-8 DED subfamily proteins.

The purpose of this study is to report the effect of Korean medicine on a squamous cell lung cancer patient with chemotherapy induction peripheral neuropathy (CIPN). A 61-year old male patient, who had received 4 cycles of chemotherapy after lung surgery from squamous cell lung cancer, was treated with acupuncture and herbal medicines, including Uchasingi-hwan and Samchilchoongcho-capsule, to control CIPN and dyspnea on exertion. The degree of pain was assessed by a numeric rating scale (NRS). After receiving acupuncture and herbal medicines, the NRS score for CIPN symptoms was reduced from 4 to 1 and the NRS score for dyspnea on exertion decreased from 3 to less than 1. Korean medicine could therefore be useful in reducing peripheral neuropathy occurring after chemotherapy and dyspnea after lobectomy.

Purpose: The aim of this study was to report the improvement of Guillain-Barre syndrome after long-term combination treatment with Korean medicine.Methods: A patient was diagnosed with Guillain-Barre syndrome and treated with herbal medicine, acupuncture, pharmacopuncture, moxibustion, and exercise, including quadruped walking after three hospital admissions. To evaluate muscle strength and weakness, we measured manual muscle function, gait pattern, and the speed of quadruped walking.Results: The patient's muscle weakness in the extremities and gait stance were improved. The speed of quadruped walking was increased.Conclusion: We consider that combined treatment with Korean medicine might be effective for the muscle weakness of Guillain-Barre syndrome with a poor prognostic factor. To verify the effectiveness of this treatment, further research is needed.

Objective: This study evaluated a clinical case of a patient with Rovazet-induced abnormal liver function treated with intradermal acupuncture.Method: A 59-year-old woman with abnormal liver function induced by Rovazet ceased taking the drug and instead received intradermal acupuncture treatment. After 15 days, clinical symptoms and laboratory test results were evaluated.Results: Aspartate aminotransferase and alanine aminotransferase levels decreased, and clinical symptoms such as nausea and fatigue improved after treatment with intradermal acupuncture and cessation of the Rovazet.Conclusion: This study meaningfully examined a clinical case of a patient with abnormal liver function induced by a lipid-lowering agent, which is uncommon in Korea. Unfortunately, the lack of clear evidence and the use of only one case are limitations of the study.

Objectives: The purpose of this study was to review the status of numeric rating scale (NRS) usage and suggest the potential for use in multicenter retrospective studies of various diseases.Methods: Articles published from 2011 to 2021 that used the keywords “NRS", “Multi-center", and “RCT" were identified in foreign databases, including EMBASE, PubMed, CENTRAL. The articles were analyzed according to their use of "NRS" by symptoms and by disease group using the major classifications of the Korean Standard Classification of Diseases (KCD-7).Results: Classification by symptom in a total of 288 articles illustrates that the NRS was not only commonly used in pain evaluation but also for non-pain symptoms. In usage with non-pain symptoms, chief complaint of patients was the most common at 79%, and other factors included treatment satisfaction, evaluation of daily life, and sleep quality. In disease classification according to the KCD-7, the NRS was commonly used in connection with musculoskeletal and connective tissue diseases but was also utilized in various other disease groups.Conclusions: This study confirms usage of the NRS in multi-center RCTs, as the NRS was widely used in all types of diseases and symptoms. Considering the result and the advantages of the NRS, it is recommended for use as a daily evaluation tool for the collection of common data in multicenter retrospective studies.

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a rare malignant neoplasm with epidermoid and glandular differentiation, accompanied by prominent sclerosis along with eosinophilic infiltration. SMECE was first described in 1991 (1) as a distinctive low-grade carcinoma of the thyroid. SMECE shows a female predilection and is associated with Hashimoto's thyroiditis (HT). (2) Cytologic descriptions of SMECE are scant and only five case reports (six cases) with cytologic findings from aspiration specimens have been described. (3-7) Because of the rarity of SMECE, no definitive cytologic criteria have been established. We describe one case of SMECE with an emphasis on the cytomorphologic features. The findings could help inform the cytologic diagnosis of SMECE.

The Medical Information Department of a pharmaceutical manufacturer provides written scientific responses to unsolicited requests from healthcare providers for information on products that extends beyond the product labeling (off-label). These scientific response documents are non-promotional, evidence-based, and scientifically balanced, conforming with internal pharmaceutical manufacturer's procedures and the Food and Drug Administration (FDA) Draft Guidance on Responding to Unsolicited Requests for Off-Label Information. Members of phactMI™ developed this proposal to offer best practices for content generation of scientific response documents. Scientific response documents review available literature to respond to an unsolicited request; therefore, they are similar in nature to systematic reviews. The sections and elements identified in this proposed best practice guidelines for scientific response documents are based on an adaptation of the sections and elements of systematic reviews. The sections of a scientific response document should include a restatement of the unsolicited request (title); a structured summary (abstract); approved indications, black box warnings, and background information when appropriate (introduction); the literature search information and study selection (methods); summation of data from clinical trials, meta-analysis, case reports, and/or real world evidence, as appropriate (results); treatment guidelines, if applicable and available (discussion); and references. Elements for each section should be included in a scientific response document as appropriate, as some elements are not necessary in some documents, based on the question. These elements were selected for inclusion to address any potential concerns of bias and transparency and reflect the intent that scientific response documents should be non-promotional, accurate, truthful, free of commercial bias, scientifically balanced, and evidence based.

Angiogenesis should be precisely regulated because disordered neovascularization is involved in the aggravation of multiple diseases. The vascular endothelial growth factor (VEGF)-A/VEGF receptor 2 (VEGFR-2) axis is crucial for controlling angiogenic responses in vascular endothelial cells (ECs). Therefore, inactivating VEGFR-2 signaling may effectively suppress aberrant angiogenesis and alleviate related symptoms. In this study, we performed virtual screening, identified the synthetic disaccharide 6′-sialylgalactose (6SG) as a potent VEGFR-2-binding compound and verified its high binding affinity by Biacore assay. 6SG effectively suppressed VEGF-A-induced VEGFR-2 phosphorylation and subsequent in vitro angiogenesis in HUVECs without inducing cytotoxicity. 6SG also inhibited VEGF-A-induced extracellular-regulated kinase (ERK)/Akt activation and actin stress fiber formation in HUVECs. We demonstrated that 6SG inhibited retinal angiogenesis in a mouse model of retinopathy of prematurity and tumor angiogenesis in a xenograft mouse model. Our results suggest a potential therapeutic benefit of 6SG in inhibiting angiogenesis in proangiogenic diseases, such as retinopathy and cancer., Abnormal blood vessel formation: Synthetic disaccharide shows therapeutic promise Therapy based on a synthetic molecule can block abnormal blood vessel formation, limiting the progression of diabetic eye conditions and tumor growth in mice. The growth of new blood vessels from existing vessels, called angiogenesis, is critical to wound healing and embryonic development. The main angiogenesis signalling pathway involves growth factors, including one called VEGFR-2. Disruption to this pathway plays a significant part in the development of multiple diseases. A South Korean team led by Ki-Tae Ha at Pusan National University, Yangsan, and Young Jun Koh at Dongguk University, Seoul, identified and trialed a synthetic disaccharide capable of binding to and limiting the activity of VEGFR-2 during faulty signaling. Trials on mice with the diabetic eye condition retinopathy, and mice with implanted tumors, showed that the compound inhibited excessive angiogenesis and limited disease progression.

The Warburg effect, wherein cancer cells prefer glycolysis rather than oxidative phosphorylation even under normoxic conditions, is a major characteristic of malignant tumors. Lactate dehydrogenase A (LDHA) is the main enzyme regulating the Warburg effect, and is thus, a major target for novel anti-cancer drug development. Through our ongoing screening of novel inhibitors, we found that several selenobenzene compounds have inhibitory effects on LDHA activity. Among them, 1-(phenylseleno)-4-(trifluoromethyl) benzene (PSTMB) had the most potent inhibitory effect on the enzymatic activity of LDHA. The results from biochemical assays and computational modeling showed that PSTMB inhibited LDHA activity. In addition, PSTMB inhibited the growth of several tumor cell lines, including NCI-H460, MCF-7, Hep3B, A375, HT29, and LLC. In HT29 human colon cancer cells, PSTMB dose-dependently inhibited the viability of the cells and activity of LDHA, without affecting the expression of LDHA. Under both normoxic and hypoxic conditions, PSTMB effectively reduced LDHA activity and lactate production. Furthermore, PSTMB induced mitochondria-mediated apoptosis of HT29 cells via production of reactive oxygen species. These results suggest that PSTMB may be a novel candidate for development of anti-cancer drugs by targeting cancer metabolism.

PUMA (p53-upregulated modulator of apoptosis) is localized in mitochondria and a direct target in p53-mediated apoptosis. p53 elicits mitochondrial apoptosis via transcription-dependent and independent mechanisms. p53 is known to induce apoptosis via the transcriptional induction of PUMA, which encodes proapoptotic BH3-only members of the Bcl-2 protein family. However, the transcription-independent mechanisms of human PUMA remain poorly defined. For example, it is not known whether PUMA interacts directly with the DNA binding domain (DBD: residues 92–293) of p53 in vitro. Here, the structure of the complex between the DBD of p53 and PUMA peptide was elucidated by X-ray crystallography. Isothermal titration calorimetry showed that PUMA peptide binds strongly with p53 DBD, and the crystal structure of p53-PUMA peptide complex revealed it contains four molecules of p53 DBD and one PUMA peptide per asymmetric unit in space group P1. PUMA peptide bound to the N-terminal residues of p53 DBD. A cell proliferation assay demonstrated PUMA peptide inhibited the growth of a lung cancer cell line. These results contribute to understanding of the mechanism responsible for p53-mediated apoptosis.

In cancer cells, aerobic glycolysis rather than oxidative phosphorylation (OxPhos) is generally preferred for the production of ATP. In many cancers, highly expressed pyruvate dehydrogenase kinase 1 (PDK1) reduces the activity of pyruvate dehydrogenase (PDH) by inducing the phosphorylation of its E1&alpha, subunit (PDHA1) and subsequently, shifts the energy metabolism from OxPhos to aerobic glycolysis. Thus, PDK1 has been regarded as a target for anticancer treatment. Here, we report that ilimaquinone (IQ), a sesquiterpene quinone isolated from the marine sponge Smenospongia cerebriformis, might be a novel PDK1 inhibitor. IQ decreased the cell viability of human and murine cancer cells, such as A549, DLD-1, RKO, and LLC cells. The phosphorylation of PDHA1, the substrate of PDK1, was reduced by IQ in the A549 cells. IQ decreased the levels of secretory lactate and increased oxygen consumption. The anticancer effect of IQ was markedly reduced in PDHA1-knockout cells. Computational simulation and biochemical assay revealed that IQ interfered with the ATP binding pocket of PDK1 without affecting the interaction of PDK1 and the E2 subunit of the PDH complex. In addition, similar to other pyruvate dehydrogenase kinase inhibitors, IQ induced the generation of mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in the A549 cells. The apoptotic cell death induced by IQ treatment was rescued in the presence of MitoTEMPO, a mitochondrial ROS inhibitor. In conclusion, we suggest that IQ might be a novel candidate for anticancer therapeutics that act via the inhibition of PDK1 activity.