DNA Checkpoint Gene Mutation as a Biomarker for Immune Checkpoint Inhibitor Therapy in Advanced Biliary Tract Cancer.

BACKGROUND/AIM: The DNA checkpoint (DNACHK) pathway is engaged in signaling the need for cell cycle arrest. This pathway is being actively researched to assess its role in cancer immunotherapy. PATIENTS AND METHODS: A total of 62 patients participated in this study. These patients were treated with immune checkpoint inhibitors (ICIs) for advanced biliary tract cancers (BTCs) from March 2020 to August 2022 at Samsung Medical Center. DNACHK mutated were defined as genomic alterations, such as single nucleotide variants, multi-nucleotide variants, and short insertion and deletions in seven genes; checkpoint kinase 1 (CHEK1), checkpoint kinase 2 (CHEK2), BRCA1, DNA repair-associated (BRCA1), the serine/threonine kinase ATM, the serine/threonine kinase ATR, mediator of DNA damage checkpoint 1 (MDC1) and tumor protein p53 binding protein 1 (TP53BP1). We analyzed the effect of DNACHK mutations on the efficacy of ICIs in advanced BTCs. RESULTS: Patient median age at diagnosis was 68.0 years. 10 patients (16.1%) had GB cancer; the remaining patients (n=52, 83.9%) were diagnosed with cholangiocarcinoma. Thirty-seven (59.7%) patients were categorized into the DNACHK wild-type (WT) group and 25 (40.3%) into the DNACHK mutated (MT) group. The most observed DNA checkpoint mutations were ATM mutations (n=14). Patients in the DNACHK MT group had better disease control rate (DCR) than patients in the DNACHK WT (60.0% vs. 48.6%, p=0.53). Median overall survival (OS) was 8.1 months (95% CI 5.1-22.8) in the MT group and 5.6 months (95%CI 3.1-11.0) in the WT group (p=0.33). CONCLUSION: The DNACHK pathway is expected to serve as a potential biomarker for ICI treatment.

Effect of COVID-19 infection and vaccination on SARS-CoV-2 antibody titer change following ovarian stimulation: Prospective analysis of IVF outcomes.

The coronavirus disease 2019 (COVID-19) outbreak caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) has affected various medical fields worldwide. However, relatively few studies have examined the impact of COVID-19 infection and vaccination on in vitro fertilization (IVF) outcomes and changes in SARS-CoV-2 antibody concentration in follicular fluid (FF). A total of 45 women were prospectively recruited and assigned to 3 groups: uninfected and non-vaccinated control group (Control group), infected group (COVID + group), and vaccinated group (Vaccination group). Serum and follicular fluid (FF) estradiol, progesterone, and SARS-CoV-2 antibody concentrations were measured. There were no statistical differences in the total number of retrieved oocytes (P = .291), mature oocytes (P = .416), and good-quality embryos (P = .694) among the 3 groups. In the vaccination group, BNT162b2 exhibited a significantly lower trigger-day serum estradiol/MII oocyte level (110.6 pg/mL) than other vaccines (289.5 pg/mL) (P = .006). No statistical differences in serum (P = .687) and FF (P = .108) SARS-CoV-2 antibody changes were noted among the 3 groups. Only FF antibody changes exhibited statistically significant differences between the BNT162b2 and other vaccine subgroups (P = .047). COVID-19 infection and vaccination do not affect IVF outcomes. However, the effect of BNT162b2 on steroidogenesis of the mature oocyte and FF SARS-CoV2 antibody titer should be further investigated.

Successful pregnancy outcome via in-vitro fertilization and laparoscopic resection of non-communicating rudimentary horn pregnancy containing early pregnancy: a case report.

BACKGROUND: Non-communicating rudimentary horn pregnancy (NCRHP) lead to life-threatening condition for both mother and fetus. Early diagnosis of NCRHP and laparoscopic resection is important to prevent catastrophic conditions. However, delayed diagnosis until the second or third trimester makes it difficult to accurately diagnose between NCRHP and bicornuate uterine pregnancy, as both conditions present uterine rupture and massive hemoperitoneum. Furthermore, these rare cases are challenging in pregnancy trials and associated with adverse outcomes in subsequent pregnancies. CASE PRESENTATION: A 31-year-old gravida 1 para 0 Korean woman visited our infertility center with a confirmed positive urine pregnancy test after timed intercourse. Before she was scheduled to have timed intercourse, a unicornuate uterus with a non-communicating right uterine horn was suspected based on an ultrasound scan and hysterosalpingography during the initial infertility workup. A gestational sac was observed in the right non-communicating rudimentary horn at 5 weeks of gestation. Serum beta-human chorionic gonadotropin (b-hCG) level was 2052.0mIU/mL. An elective laparoscopic resection of the right rudimentary horn containing a gestational sac, along with ipsilateral salpingectomy, was performed with no adverse event. After 3-month of recovery period and three cycles of conceptional trials involving timed intercourse and intrauterine insemination, in-vitro fertilization (IVF) was performed using the antagonist protocol, and successful pregnancy was confirmed. The patient had been hospitalized from 21 + 6 weeks to 35 + 6 weeks of gestation, underwent cerclage placement and tocolytics with corticosteroid treatment. She delivered an early-term male baby by cesarean section. CONCLUSION: In this rare case, the successful pregnancy achieved through IVF following the appropriate management of NCRHP under laparoscopy underscores the critical importance of early diagnosis and intervention in cases of NCRHP. Timely identification and management of NCRHP are vital to prevent the occurrence of catastrophic conditions and to enhance the prognosis of a successful pregnancy through assisted reproductive technology (ART). Therefore, a high index of suspicion for NCRHP is important and employs a range of diagnostic modalities.

Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia.

BACKGROUND: Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML. METHODS: We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients. RESULTS: We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models. CONCLUSION: Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.

Clinical Outcomes of Upfront Primary Tumor Resection in Synchronous Unresectable Metastatic Colorectal Cancer.

The role of upfront primary tumor resection (PTR) in patients with unresectable metastatic colorectal cancer without severe symptoms remains controversial. We retrospectively analyzed the role of PTR in overall survival (OS) in this population. Among the 205 patients who enrolled, the PTR group (n = 42) showed better performance (p = 0.061), had higher frequencies of right-sided origin (p = 0.058), the T4 stage (p = 0.003), the M1a stage (p = 0.012), and <2 organ metastases (p = 0.002), and received fewer targeted agents (p = 0.011) than the chemotherapy group (n = 163). The PTR group showed a trend for longer OS (20.5 versus 16.0 months, p = 0.064) but was not related to OS in Cox regression multivariate analysis (p = 0.220). The male sex (p = 0.061), a good performance status (p = 0.078), the T3 stage (p = 0.060), the M1a stage (p = 0.042), <2 organ metastases (p = 0.035), an RAS wild tumor (p = 0.054), and the administration of targeted agents (p = 0.037), especially bevacizumab (p = 0.067), seemed to be related to PTR benefits. Upfront PTR could be considered beneficial in some subgroups, but these findings require larger studies to verify.

Survey-Based Analysis of the Clinical Treatment Status of Irritable Bowel Syndrome in Korea.

BACKGROUND: The quality-of-life of patients with irritable bowel syndrome is low; incorrect diagnosis/treatment causes economic burden and inappropriate consumption of medical resources. This survey-based study aimed to analyze the current status of irritable bowel syndrome treatment to examine differences in doctors' perceptions of the disease, and treatment patterns. METHODS: From October 2019 to February 2020, the irritable bowel syndrome and Intestinal Function Research Study Group of the Korean Society of Neurogastroenterology and Motility conducted a survey on doctors working in primary, secondary, and tertiary healthcare institutions. The questionnaire included 37 items and was completed anonymously using the NAVER platform (a web-based platform), e-mails, and written forms. RESULTS: A total of 272 doctors responded; respondents reported using the Rome IV diagnostic criteria (amended in 2016) for diagnosing and treating irritable bowel syndrome. Several differences were noted between the primary, secondary, and tertiary physicians' groups. The rate of colonoscopy was high in tertiary healthcare institutions. During a colonoscopy, the necessity of random biopsy was higher among physicians who worked at tertiary institutions. 'The patient did not adhere to the diet' as a reason for ineffectiveness using low-fermentable oligo-, di-, and mono-saccharides, and polyols diet treatment was higher among physicians in primary/secondary institutions, and 'There are individual differences in terms of effectiveness' was higher among physicians in tertiary institutions. In irritable bowel syndrome constipation predominant subtype, the use of serotonin type 3 receptor antagonist (ramosetron) and probiotics was higher in primary/secondary institutions, while serotonin type 4 receptor agonist was used more in tertiary institutions. In irritable bowel syndrome diarrhea predominant subtype, the use of antispasmodics was higher in primary/secondary institutions, while the use of serotonin type 3 receptor antagonist (ramosetron) was higher in tertiary institutions. CONCLUSION: Notable differences were observed between physicians in primary/secondary and tertiary institiutions regarding the rate of colonoscopy, necessity of random biopsy, the reason for the ineffectiveness of low-fermentable oligo-, di-, and mono-saccharides, and polyols diet, and use of drug therapy in irritable bowel syndrome. In South Korea, irritable bowel syndrome is diagnosed and treated according to the Rome IV diagnostic criteria, revised in 2016.

Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination.

BACKGROUND: Although metastasis is the foremost cause of cancer-related death, a specialized mechanism that reprograms anchorage dependency of solid tumor cells into circulating tumor cells (CTCs) during metastatic dissemination remains a critical area of challenge. METHODS: We analyzed blood cell-specific transcripts and selected key Adherent-to-Suspension Transition (AST) factors that are competent to reprogram anchorage dependency of adherent cells into suspension cells in an inducible and reversible manner. The mechanisms of AST were evaluated by a series of in vitro and in vivo assays. Paired samples of primary tumors, CTCs, and metastatic tumors were collected from breast cancer and melanoma mouse xenograft models and patients with de novo metastasis. Analyses of single-cell RNA sequencing (scRNA-seq) and tissue staining were performed to validate the role of AST factors in CTCs. Loss-of-function experiments were performed by shRNA knockdown, gene editing, and pharmacological inhibition to block metastasis and prolong survival. RESULTS: We discovered a biological phenomenon referred to as AST that reprograms adherent cells into suspension cells via defined hematopoietic transcriptional regulators, which are hijacked by solid tumor cells to disseminate into CTCs. Induction of AST in adherent cells 1) suppress global integrin/ECM gene expression via Hippo-YAP/TEAD inhibition to evoke spontaneous cell-matrix dissociation and 2) upregulate globin genes that prevent oxidative stress to acquire anoikis resistance, in the absence of lineage differentiation. During dissemination, we uncover the critical roles of AST factors in CTCs derived from patients with de novo metastasis and mouse models. Pharmacological blockade of AST factors via thalidomide derivatives in breast cancer and melanoma cells abrogated CTC formation and suppressed lung metastases without affecting the primary tumor growth. CONCLUSION: We demonstrate that suspension cells can directly arise from adherent cells by the addition of defined hematopoietic factors that confer metastatic traits. Furthermore, our findings expand the prevailing cancer treatment paradigm toward direct intervention within the metastatic spread of cancer.

Orientation of the ultrasound probe to identify the taller-than-wide sign of thyroid malignancy: a registry-based study with the Thyroid Imaging Network of Korea.

PURPOSE: Although the taller-than-wide (TTW) sign has been regarded as one of the most specific ultrasound (US) features of thyroid malignancy, uncertainty still exists regarding the US probe's orientation when evaluating it. This study investigated which US plane would be optimal to identify the TTW sign based on malignancy risk stratification using a registry-based imaging dataset. METHODS: A previous study by 17 academic radiologists retrospectively analyzed the US images of 5,601 thyroid nodules (≥1 cm, 1,089 malignant and 4,512 benign) collected in the webbased registry of Thyroid Imaging Network of Korea through the collaboration of 26 centers. The present study assessed the diagnostic performance of the TTW sign itself and fine needle aspiration (FNA) indications via a comparison of four international guidelines, depending on the orientation of the US probe (criterion 1, transverse plane; criterion 2, either transverse or longitudinal plane). RESULTS: Overall, the TTW sign was more frequent in malignant than in benign thyroid nodules (25.3% vs. 4.6%). However, the statistical differences between criteria 1 and 2 were negligible for sensitivity, specificity, and area under the curve (AUC) based on the size effect (all P<0.05, Cohen's d=0.19, 0.10, and 0.07, respectively). Moreover, the sensitivity, specificity, and AUC of the four FNA guidelines were similar between criteria 1 and 2 (all P>0.05, respectively). CONCLUSION: A longitudinal US probe orientation provided little additional diagnostic value over the transverse orientation in detecting the TTW sign of thyroid nodules.

Efficacy of dabrafenib/trametinib in pancreatic ductal adenocarcinoma with BRAF NVTAP deletion: A case report.

Studies have been actively conducted to identify actionable mutations and incorporate them into clinical practice in pancreatic ductal adenocarcinoma (PDAC), which is known to have a poor prognosis with traditional cytotoxic chemotherapy. A BRAF point mutation in V600E is commonly reported in KRAS wild-type PDAC, and targeting BRAF_V600E is already being applied to various carcinomas, including PDAC. Accumulated evidence also shows that not only BRAF_V600E but also short in-frame deletions of BRAF have an oncogenic function. Here, we report that a patient with BRAF N486_P490 deletion initiated on dabrafenib or trametinib, a BRAF inhibitor, and a MEK inhibitor, respectively, after cytotoxic chemotherapy failure. The patient then presented with a partial response.

Usefulness of the delta neutrophil index in predicting surgery in patients with foot and ankle infection.

BACKGROUND: In foot and ankle infections, cases with apparent soft-tissue necrosis or purulent fluid collections definitely require surgical treatments. However, clinicians often have difficulty in determining whether to perform surgery in ambiguous cases without these findings. This study aimed to investigate the impact of the delta neutrophil index as a predictor of surgical treatment in patients with foot and ankle infections. METHODS: In total, 66 patients diagnosed with foot and ankle infections who underwent the delta neutrophil index test were retrospectively investigated. Medical records, including data on diabetes mellitus status, delta neutrophil index values, white blood cell count, polymorphonuclear leukocyte count, erythrocyte sedimentation rate, and C-reactive protein level, were retrospectively investigated. Logistic regression models were analyzed for the correlation between biomarkers, such as the delta neutrophil index and surgical treatment. The area under the curve was investigated to evaluate the cut-off value of the logistic model in predicting surgery. RESULTS: The relationship between the delta neutrophil index and surgical treatment was analyzed. The delta neutrophil index, adjusted for diabetes mellitus, was the best predictor of future surgical intervention. Based on the Youden index, the cutoff point (the equation's adjusted by diabetes mellitus) for the prediction of surgical treatment was defined as a probability of 0.3, with sensitivity and specificity of 82.4% and 77.6%, respectively. CONCLUSIONS: Based on the present study, the delta neutrophil index can help clinicians decide the appropriate surgical treatment for foot and ankle infections at the right time.

Discovery of indirubin-3'-aminooxy-acetamide derivatives as potent and selective FLT3/D835Y mutant kinase inhibitors for acute myeloid leukemia.

Mutations in Fms-like tyrosine kinase 3 (FLT3) have been implicated in the pathogenesis of acute myeloid leukemia (AML) by affecting the proliferation and differentiation of hematopoietic stem and progenitor cells. Although several FLT3 inhibitors have been developed, the occurrence of secondary TKD mutations of FLT3 such FLT3/D835Y and FLT3/F691L lead to drug resistance and has become a key area of unmet medical needs. To overcome the obstacle of secondary TKD mutations, a new series of indirubin-3'-aminooxy-acetamide derivatives was discovered as potent and selective FLT3 and FLT3/D835Y inhibitors that were predicted to bind at the DFG-in active conformation of FLT3 in molecular docking studies. Through structure-activity relationship studies, the most optimized compound 13a was developed as a potent inhibitor at FLT3 and FLT3/D835Y with IC50 values of 0.26 nM and 0.18 nM, respectively, which also displayed remarkably strong in vitro anticancer activities, with single-digit nanomolar GI50 values for several AML (MV4-11 and MOLM14) and Ba/F3 cell lines expressed with secondary TKD mutated FLT3 kinases as well as FLT3-ITD. The selectivity profiles of compound 13a in the oncology kinase panel and various human cancer cell lines were prominent, demonstrating that its inhibitory activities were mainly focused on a few members of the receptor tyrosine kinase family and AML versus solid tumor cell lines. Furthermore, significant in vivo anticancer efficacy of compound 13a was confirmed in a xenograft animal model implanted with FLT3-ITD/D835Y-expressing MOLM-14 cells related to secondary TKD mutation.

Additional Excision Biopsy in Patients With Atypical Ductal Hyperplasia at Ultrasound-guided Vacuum-assisted Breast Biopsy.

BACKGROUND/AIM: We conducted this single-center, retrospective study to identify predictors of upgrading to malignancy and to discuss the necessity of additional excision biopsy in patients who were diagnosed with atypical ductal hyperplasia (ADH) at ultrasound (US)-guided vacuum-assisted breast biopsy (VABB) based on our 18-year, single-center experience. PATIENTS AND METHODS: The current study was conducted in a total of 12,160 patients who were evaluated at our medical institution during an 18-year period between January of 2003 and December of 2020. We included the patients who were diagnosed with ADH at US-guided VABB using the Mammotome® (Devicor Medical Products, Inc., Cincinnati, OH, USA). We therefore included a total of 114 patients (n=114) with ADH in the current study. RESULTS: Of 114 eligible patients, 36 underwent additional excision biopsy and the remaining 78 did not. Of these 36 patients, 15 were found to have an upgrading to malignancy at a rate of upgrading of 41.7%. These include 7 cases (46.6%) of low-grade ductal carcinoma in situ (DCIS), 3 cases (20.0%) of intermediate grade DCIS, 1 case (6.7%) of microinvasive DCIS, 3 cases (20.0%) of multifocal lobular carcinoma in situ, and 1 case (6.7%) of mucinous carcinoma. Finally, only suspicious microcalcification on mammography was a significant predictor of upgrading to malignancy (p=0.023). CONCLUSION: An additional excision biopsy is recommended to reduce the rate of upgrading to malignancy in patients who were diagnosed with ADH through a US-guided VABB.

Ginsenoside Re exhibits neuroprotective effects by inhibiting neuroinflammation via CAMK/MAPK/NF­κB signaling in microglia.

Ginsenoside Re (G­Re) is a panaxatriol saponin and one of the pharmacologically active natural constituents of ginseng (Panax ginseng C.A. Meyer). G­Re has antioxidant, anti­inflammatory and antidiabetic effects. The present study aimed to investigate the effects of G­Re on neuroinflammatory responses in lipopolysaccharide (LPS)­stimulated microglia and its protective effects on hippocampal neurons. Cytokine levels were measured using ELISA and reactive oxygen species (ROS) levels were assessed using flow cytometry and fluorescence microscopy. Protein levels of inflammatory molecules and kinase activity were assessed by western blotting. Cell viability was assessed by MTT assay; apoptosis was estimated by Annexin V apoptosis assay. The results revealed that G­Re significantly inhibited the production of IL­6, TNF­α, nitric oxide (NO) and ROS in BV2 microglial cells, and that of NO in mouse primary microglia, without affecting cell viability. G­Re also inhibited the nuclear translocation of NF­κB, and phosphorylation and degradation of IκB­α. In addition, G­Re dose­dependently suppressed LPS­mediated phosphorylation of Ca2+/calmodulin­dependent protein kinase (CAMK)2, CAMK4, extracellular signal­regulated kinase (ERK) and c­Jun N­terminal kinases (JNK). Moreover, the conditioned medium from LPS­stimulated microglial cells induced HT22 hippocampal neuronal cell death, whereas that from microglial cells incubated with both LPS and G­Re ameliorated HT22 cell death in a dose­dependent manner. These results suggested that G­Re suppressed the production of pro­inflammatory mediators by blocking CAMK/ERK/JNK/NF­κB signaling in microglial cells and protected hippocampal cells by reducing these inflammatory and neurotoxic factors released from microglial cells. The present findings indicated that G­Re may be a potential treatment option for neuroinflammatory disorders and could have therapeutic potential for various neurodegenerative diseases.

Soluble Whey Protein Hydrolysate Ameliorates Muscle Atrophy Induced by Immobilization via Regulating the PI3K/Akt Pathway in C57BL/6 Mice.

Sarcopenia, a loss of skeletal muscle mass and function, is prevalent in older people and associated with functional decline and mortality. Protein supplementation is necessary to maintain skeletal muscle mass and whey protein hydrolysates have the best nutrient quality among food proteins. In the first study, C57BL/6 mice were subjected to immobilization for 1 week to induce muscle atrophy. Then, mice were administered with four different whey protein hydrolysates for 2 weeks with continuous immobilization. Among them, soluble whey protein hydrolysate (WP-S) had the greatest increase in grip strength, muscle weight, and cross-sectional area of muscle fiber than other whey protein hydrolysates. To investigate the molecular mechanism, we conducted another experiment with the same experimental design. WP-S significantly promoted the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway and inhibited the PI3K/Akt/forkhead box O (FoxO) pathway. In addition, it increased myosin heavy chain (MyHC) expression in both the soleus and quadriceps and changed MyHC isoform expressions. In conclusion, WP-S attenuated muscle atrophy induced by immobilization by enhancing the net protein content regulating muscle protein synthesis and degradation. Thus, it is a necessary and probable candidate for developing functional food to prevent sarcopenia.

Dietary Protein to Carbohydrate Ratio and Incidence of Metabolic Syndrome in Korean Adults Based on a Long-Term Prospective Community-Based Cohort.

Interest in high protein diets has recently been increasing for reduction of weight or management of cardiometabolic risks. However, studies on high protein, low carbohydrate diet in Asians are limited. This study aimed to estimate whether the dietary ratio of protein (%) to carbohydrate (%) from total energy intake (p/c ratio) is associated with the risk of metabolic syndrome (MS) and its components in Korean adults using a long-term prospective cohort. A total of 6335 participants from the Korean Genome and Epidemiology Study, aged between 40 and 69 years, with no previous diagnosis of MS, cardiovascular diseases, or cancer at baseline (2001-2002) were followed until 2013. Dietary intake was measured using a validated semiquantitative food-frequency questionnaire. MS components were measured at baseline and every 2 years. During a mean of 7.7 years of follow up, 1198 (36.1%) men and 1169 (38.8%) women developed MS. The multivariate adjusted hazard ratio (HR) of incident MS was 1.43 (95% confidence interval, 1.09-1.89) for the highest compared lowest quintile of p/c ratio in men. When evaluating each component of MS, higher dietary p/c ratio was associated with an increased risk of high triglyceride and fasting glucose in men (HR for fifth vs. first quintile, 1.39 and 1.41 in Model 3, respectively). However, we observed no associations with incident MS and its components and dietary p/c ratio in women. In conclusion, we found that high dietary p/c ratio was associated with an increased risk of MS and its components (i.e., increased triglycerides and fasting glucose) in men. Our study suggested that even if the absolute amount of protein intake is not large, an increased p/c ratio may increase the risk of metabolic diseases.

Discovery of orally active indirubin-3'-oxime derivatives as potent type 1 FLT3 inhibitors for acute myeloid leukemia.

FMS-like receptor tyrosine kinase-3 (FLT3) is expressed on acute leukemia cells and is implicated in the survival, proliferation and differentiation of hematopoietic cells in most acute myeloid leukemia (AML) patients. Despite recent achievements in the development of FLT3-targeted small-molecule drugs, there are still unmet medical needs related to kinase selectivity and the progression of some mutant forms of FLT3. Herein, we describe the discovery of novel orally available type 1 FLT3 inhibitors from structure-activity relationship (SAR) studies for the optimization of indirubin derivatives with biological and pharmacokinetic profiles as potential therapeutic agents for AML. The SAR exploration provided important structural insights into the key substituents for potent inhibitory activities of FLT3 and in MV4-11 cells. The profile of the most optimized inhibitor (36) showed IC50 values of 0.87 and 0.32 nM against FLT3 and FLT3/D835Y, respectively, along with potent inhibition against MV4-11 and FLT3/D835Y expressed MOLM14 cells with a GI50 value of 1.0 and 1.87 nM, respectively. With the high oral bioavailability of 42.6%, compound 36 displayed significant in vivo antitumor activity by oral administration of 20 mg/kg once daily dosing schedule for 21 days in a mouse xenograft model. The molecular docking study of 36 in the homology model of the DFG-in conformation of FLT3 resulted in a reasonable binding mode in type 1 kinases similar to the reported type 1 FLT3 inhibitors Crenolanib and Gilteritinib.

Effect of Autologous Adipose-Derived Stromal Vascular Fraction Transplantation on Endometrial Regeneration in Patients of Asherman's Syndrome: a Pilot Study.

This study aimed to investigate the efficacy of the transplantation of autologous adipose-derived stromal vascular fraction (AD-SVF) containing adipose stem cells (ASCs) in regenerating functional endometrium in patients with severe Asherman's syndrome (AS). This was a prospective clinical study involving six infertile women aged 20-44 years who were diagnosed with severe AS by hysteroscopy. Autologous AD-SVF were isolated from patient's adipose tissue obtained by liposuction and then transplanted into uterus by transcervical instillation using an embryo transfer catheter followed by estrogen hormone therapy. Endometrial growth and pregnancy outcomes were assessed after fresh or frozen embryo transfer. Of the five patients who remained in the study, two women who had amenorrhea resumed their menstruation with irregular scant bleeding. Three women with oligomenorrhea had increased menstrual amount. Before therapy, the maximum EMT measured ultrasonographically was 3.0 ± 1.0 mm (range: 1.7 to 4.4 mm), which significantly increased to 6.9 ± 2.9 mm (range: 5.2 to 12.0 mm, p = 0.043) after cell transplantation and hormone therapy. Five women had embryo transfer after therapy: one fresh and four frozen-thawed. One woman conceived but aborted spontaneously at 9-week gestation. AD-SVF is a safe and easily available cell product containing adipose-derived stem cells. Autologous transplantation of AD-SVF may regenerate damaged human endometrium and increase endometrial receptivity. Our study showed the feasibility of AD-SVF in restoring endometrial function and increasing endometrial thickness. This cell therapy may become a promising treatment for infertile women with endometrial dysfunction and needs further investigation.

Changing patterns of adult asthma incidence: results from the National Health Insurance Service-National Sample Cohort (NHIS-NSC) database in Korea.

This study was conducted to assess the changes in the annual incidence of adult asthma in Korea where the prevalence of asthma had increased steadily in recent decades. A population-based cohort study was conducted using the National Health Insurance Service-National Sample Cohort (NHIS-NSC), which consisted of 746,816 adults aged >20 years between 2004 and 2012. Asthma was defined by two or more physician claims on the basis of a primary diagnostic code for asthma and administration of asthma medications within 1 year. The incidence rates and annual percent change were calculated, and the influence of age and sex on the incidence rates was studied. The annual asthma incidence increased from 3.63 in 2004 to 6.07 per 1,000 person-years in 2008. Since 2008, the asthma incidence did not change significantly. The asthma incidence was higher in women than in men throughout the study periods (p < 0.001) and higher in older than younger age groups (p < 0.001). The asthma incidence did not change in all ages since 2008, except for the 20 s who showed a steady increase. The incidence of asthma in adults reached plateau in Korea, which is consistent with the results from studies in other countries.