Effectiveness and Usefulness of Bone Turnover Marker in Osteoporosis Patients: A Multicenter Study in Korea.

BACKGROUND: This study aimed to investigate real-world data of C-terminal telopeptide (CTX), propeptide of type I collagen (P1NP), and osteocalcin through present multicenter clinical study, and retrospectively analyze the usefulness of bone turnover markers (BTMs) in Koreans. METHODS: The study focused on pre- and post-menopausal patients diagnosed with osteoporosis and excluded patients without certain test results or with test intervals of over 1 year. The demographic data and 3 BTMs (CTX, P1NP, and osteocalcin) were collected. The patients were classified by demographic characteristics and the BTM concentrations were analyzed by the group. RESULTS: Among women with no history of fractures, the levels of P1NP (N=2,100) were 43.544±36.902, CTX (N=1,855) were 0.373 ±0.927, and osteocalcin (N=219) were 10.81 ±20.631. Among men with no history of fractures, the levels of P1NP (N=221) were 48.498±52.892, CTX (N=201) were 0.370±0.351, and osteocalcin (N=15) were 7.868 ±10.674. Treatment with teriparatide increased the P1NP levels after 3 months in both men and women, with a 50% increase observed in women. Similarly, treatment with denosumab decreased the CTX levels after 3 months in both men and women, with a reduction of 50% observed in women. CONCLUSIONS: The results of this study can contribute to the accurate assessment of bone replacement status in Koreans. We also provide the P1NP level in the Korean population for future comparative studies with other populations.

Association between the Blautia/Bacteroides Ratio and Altered Body Mass Index after Bariatric Surgery.

BACKGRUOUND: Current evidence support that the gut microbiota plays a potential role in obesity. Bariatric surgery can reduce excess weight and decrease the risk of life-threatening weight-related health problems and may also influence gut microbiota. In this study, we aimed to investigate the changes in gut microbiota before and after bariatric surgery and evaluate the association of the gut microbial shift and altered body mass index (BMI) after bariatric surgery. METHODS: Between January 2019 and July 2020, stools from 58 patients scheduled for bariatric surgery were collected. Six months after bariatric surgery, stools from 22 of these patients were re-collected, and the changes in gut microbiota before and after bariatric surgery were evaluated. In addition, the differences in gut microbiota between patients with severe obesity (BMI >35 kg/m2, n=42) and healthy volunteers with normal BMI (18.8 to 22.8 kg/m2, n=41) were investigated. RESULTS: The gut microbiota of patients who underwent bariatric surgery showed increased α-diversity and differed ß-diversity compared with those before surgery. Interestingly, Blautia was decreased and Bacteriodes was increased at the genus level after bariatric surgery. Further, the Blautia/Bacteroides ratio showed a positive correlation with BMI. To validate these results, we compared the gut microbiota from severely obese patients with high BMI with those from healthy volunteers and demonstrated that the Blautia/Bacteroides ratio correlated positively with BMI. CONCLUSION: In the gut microbial analysis of patients who underwent bariatric surgery, we presented that the Blautia/Bacteroides ratio had changed after bariatric surgery and showed a positive correlation with BMI.

Changes of Guidelines in the Management of Obese Patients With Diabetes in the Metabolic Surgery Perspective.

Recently, metabolic surgery was recommended for patients with a BMI of 30 or higher and 27.5 or higher for Asians, as evidence level A. Until 2008, bariatric surgery was not introduced for the treatment of diabetes. Bariatric surgery was first recommended for adults with body mass index ≥35 kg/m2 and type 2 diabetes in the American Diabetes Association (ADA) guidelines as evidence level B in 2009. In 2017, the terminology was changed from bariatric surgery to metabolic surgery. How such large changes could have occurred in the ADA guidelines? Because many patients have reached diabetes remission through metabolic surgery, and the long-term benefit and cost-effectiveness have been strongly proven by historical randomized controlled trials and high-quality studies. This review demonstrates how the recommendations for the treatment of obesity in patients with diabetes have changed in diabetes treatment guidelines and summarizes the evidence behind this change.

Role of early short-term cardiac rehabilitation in patients undergoing pacemaker implantation.

Exercise-based cardiac rehabilitation (CR) improves the clinical outcomes in patients with cardiovascular diseases. However, few data exist regarding the role of early short-term CR in patients undergoing pacemaker (PM) implantation. We assessed whether short-term CR following PM implantation was sufficient to improve both physical function and quality of life (QOL). A total of 27 patients with a 6-minute walking distance (6MWD) of less than 85% of the predicted value on the day following PM implantation were randomly assigned to either the CR group (n = 12, 44.4%) or the non-CR group (n = 15, 55.6%). The CR group involved individualized exercise-based training with moderate intensity for 4 weeks after PM implantation. Cardiopulmonary exercise test (CPET), 6MWD, muscle strength, and Short Form (SF)-36 were assessed at baseline and at the 4-week follow-up. After a mean follow-up period of 38.3 days, both groups showed significantly improved 6MWD. Peak oxygen uptake improved in both groups on CPET, but the difference was not statistically significant. Knee extension power and handgrip strength were similar in both groups. Regarding QOL, only the CR group showed improved SF-36 scores in the items of vitality and mental health. There was no difference in any subscale in the non-CR group. Neither lead dislodgement nor significant changes in PM parameters were observed in any patient. Early short-term CR following PM implantation was associated with improved psychological subscales and can be safely performed without increasing the risk of procedure-related complications.

Impact of Fusobacterium nucleatum in the gastrointestinal tract on natural killer cells.

BACKGROUND: Gut microbial dysbiosis contributes to the development and progression of colorectal cancer (CRC). Natural killer (NK) cells are involved in early defense mechanisms to kill infective pathogens and tumor cells by releasing chemokines and cytokines. To better understand the relationship between the gut microbiome and CRC, it was hypothesized here that a high abundance of Fusobacterium nucleatum (F. nucleatum) in the gastrointestinal tract could cause reduced NK cell activity. AIM: To identify associations between gastrointestinal tract F. nucleatum levels and NK cell activity. METHODS: In vitro experiments were performed on NK cells treated with F. nucleatum, Peptostreptococcus anaerobius, and Parvimonas micra to identify the effects of gut microbiome species on NK cells. Following 24 and 48 h of treatment, NK cell counts were measured. In parallel studies, C57BL/6 mice were given broad-spectrum antibiotics in their drinking water to reduce resident gut flora. After 3 wk, the mice received the various bacterial species or phosphate-buffered saline (PBS) via oral gavage every 2 d for 6 wk. At the study end, blood samples were acquired to perform NK cell activity assessment and cytokine analysis. Intestinal tissues were collected and analyzed via immunohistochemistry (IHC). RESULTS: The data show that after 3 wk of broad-spectrum antibiotic treatment, levels of total bacteria and F. nucleatum were markedly decreased in mice. Gavage of F. nucleatum significantly decreased NK cell activity relative to the activities of cells from mice treated with antibiotics only and PBS. The administration of F. nucleatum decreased the proportion of NK46+ cells based on IHC staining and increased the production of interleukin-1ß and tumor necrosis factor-α. CONCLUSION: High levels of F. nucleatum in the gastrointestinal tract reduced NK cell activity in mice, and the decrease in NK cell activity might be affected by increased pro-inflammatory cytokines after F. nucleatum treatment.

Clinicopathological Characteristics and Recurrence-Free Survival of Rare Variants of Papillary Thyroid Carcinomas in Korea: A Retrospective Study.

BACKGROUND: We aimed to evaluate the clinicopathological features and biological behaviors of Korean thyroid cancer patients with rare variants of papillary thyroid carcinoma (PTC) to address the ambiguity regarding the prognostic consequences of these variants. METHODS: We retrospectively reviewed the medical records of 5,496 patients who underwent thyroid surgery for PTC, between January and December 2012, in nine tertiary hospitals. Rare PTC variants included tall cell (TCV), columnar cell (CCV), diffuse sclerosing (DSV), cribriform-morular (CMV), solid (SV), hobnail, and Warthin-like variants. Recurrence-free survival (RFS) was defined as the time from the date of thyroidectomy until recurrence. RESULTS: Rare variants accounted for 1.1% (n=63) of the PTC patients; with 0.9% TCV, 0.02% CCV, 0.1% DSV, 0.1% CMV, and 0.1% SV. The mean age of patients and primary tumor size were 42.1±13.1 years and 1.3±0.9 cm, respectively. Extrathyroidal extension and cervical lymph node metastasis were observed in 38 (60.3%) and 37 (58.7%) patients, respectively. Ultrasonographic findings revealed typical malignant features in most cases. During a median follow-up of 7 years, 6.3% of patients experienced a locoregional recurrence. The 5-year RFS rates were 71.4% in patients with DSV or SV, 95.9% for TCV, or CCV, and 100% for other variants. DSV emerged an independent risk factor associated with shorter RFS. CONCLUSION: In this multicenter Korean cohort, rare variants accounted for 1.1% of all PTC cases, with TCV being the most frequent subtype. DSV emerged as a significant prognostic factor for RFS.

Effectiveness of liraglutide 3 mg for the treatment of obesity in a real-world setting without intensive lifestyle intervention.

OBJECTIVE: We investigated the efficacy and safety of liraglutide 3 mg daily in combination with diet and exercise 2, 4, and 6 months after initiation in real-world settings in Korea. METHODS: People first using liraglutide starting in 2018 were recruited from ten sites in Korea. Body weight and body mass index (BMI) were measured after 2, 4, and 6 months and compared with baseline values. RESULTS: The full cohort comprised 769 participants: 672 in the 2-month group, 427 in the 4-month group, and 219 in the 6-month group. The baseline mean ± standard deviation of BMI and body weight were 32.2 ± 5.1 kg/m2, and 87.5 ± 18.8 kg, respectively. Body weight and BMI decreased after initiation of liraglutide treatment: -2.94 kg and -1.08 kg/m2 at 2 months; -4.23 kg and -1.55 kg/m2 at 4 months, and -5.14 kg and -1.89 kg/m2 at 6 months (all P < 0.001). In the 6-month cohort, 52.5% and 18.3% of subjects lost ≥5% and ≥10% of body weight, respectively. After 6 months, systolic and diastolic blood pressure decreased significantly by 3.90 and 1.93 mmHg, respectively. In those with diabetes mellitus, HbA1c and fasting glucose levels decreased significantly by 1.14% and 27.8 mg/dl, respectively. Among all participants, 27.6% experienced adverse effects, including nausea (20.8%), vomiting (5.2%), diarrhoea (2.5%), and skin rash (3.6%). Documented reasons for discontinuation of treatment were lack of effect (4.4%), adverse events (4.3%), and high cost (3.1%). CONCLUSIONS: In real-world settings in Korea, daily treatment with liraglutide 3 mg was associated with clinically meaningful weight loss without serious adverse events.

Diagnosis and Treatment of Growth Hormone Deficiency: A Position Statement from Korean Endocrine Society and Korean Society of Pediatric Endocrinology.

Growth hormone (GH) deficiency is caused by congenital or acquired causes and occurs in childhood or adulthood. GH replacement therapy brings benefits to body composition, exercise capacity, skeletal health, cardiovascular outcomes, and quality of life. Before initiating GH replacement, GH deficiency should be confirmed through proper stimulation tests, and in cases with proven genetic causes or structural lesions, repeated GH stimulation testing is not necessary. The dosing regimen of GH replacement therapy should be individualized, with the goal of minimizing side effects and maximizing clinical improvements. The Korean Endocrine Society and the Korean Society of Pediatric Endocrinology have developed a position statement on the diagnosis and treatment of GH deficiency. This position statement is based on a systematic review of evidence and expert opinions.

[Influence of self-differentiation, psychological discomfort, and marital dyadic adjustment on maternal-fetal attachment in primigravida]. / 초임부의 자기분화, ì‹¬ë¦¬ì  불편감 및 ë¶€ë¶€ì ì‘ì´ íƒœì•„ì• ì°©ì— 미치는 영향.

Purpose: The purpose of this study was to identify the influence of self-differentiation, psychological discomfort, and marital dyadic adjustment on maternal-fetal attachment in primigravida. Methods: In total, 108 primigravida participated in this descriptive correlational study. The participants answered self-report questionnaires. Data were collected from January to May, 2020, and were analyzed using descriptive statistics, the t-test, analysis of variance, Pearson correlation coefficients, and hierarchical multiple regression with SPSS for Windows ver. 23.0. Results: The mean age of the primigravida was 31.66 years. The mean score for the degree of maternal-fetal attachment was 76.81 out of 96 points. Participants' scores for maternal-fetal attachment differed significantly based on age (t=2.08 p=.039) and marital status (t=2.05, p=.043). Maternal-fetal attachment was significantly negatively correlated with psychological discomfort (r=-.39, p<.001), and significantly positively correlated with self-differentiation (r=.36, p<.001) and marital dyadic adjustment (r=.36, p<.001). Self-differentiation explained 24.1% of variance in participants' maternal-fetal attachment, and its effect was statistically significant (F=7.79, p<.001). Conclusion: In primigravida, more self-differentiation was associated with stronger maternal-fetal attachment. To strengthen maternal-fetal attachment in primigravida, educational program that increases the level of self-differentiation and minimizes their psychological discomfort may be helpful for first time pregnant women. Additionally, it is recommended to provide nursing interventions to encourage couples to work together throughout the gestational period.

Type-Specific Viral Load and Physical State of HPV Type 16, 18, and 58 as Diagnostic Biomarkers for High-Grade Squamous Intraepithelial Lesions or Cervical Cancer.

PURPOSE: High rate of false-positive tests is a major obstacle to use human papillomavirus (HPV) detection as a diagnostic tool for high-grade squamous intraepithelial lesions or cervical cancer (HSIL+). We investigated whether type-specific viral load or physical state of HPV 16, 18, and 58 are useful biomarkers for HSIL+. MATERIALS AND METHODS: Type-specific viral loads of E6 and E2 genes in cervical cells from 240, 83, and 79 HPV 16-, 18-, and 58-infected women, respectively, were determined using real-time polymerase chain reaction. Viral loads were normalized to cellular DNA (copy/cell). Total and integrated viral loads and physical state were compared between HSIL+ and controls, and diagnostic value was determined using receiver operating characteristic analysis. RESULTS: Viral loads of HPV 16, 18, and 58 were significantly different in lesions in the same pathologic grade. High type-specific total viral loads were significantly associated with HSIL+ (odds ratio [OR], 14.065, 39.472, and 7.103 for HPV 16, 18, and 58, respectively). High integrated viral load was related to HSIL+ in women with HPV 16 (OR, 8.242), and integrated state was associated with HSIL+ in women with HPV 18 (OR, 9.443). Type-specific total viral load was significantly associated with HSIL+ (area under curve, 0.914, 0.937, and 0.971 for HPV 16, 18, and 58, respectively), indicating an excellent performance in detecting HSIL+. CONCLUSION: Type-specific total viral load may be a powerful diagnostic marker for HSIL+ in HPV 16-, 18-, and 58-infected HSIL+ lesions. If demonstrated in all other high-risk HPV types, this method can lead to a paradigm shift in the strategy of equivocal cytologic abnormalities.

Relationship between ultrasonographic and pathologic calcification patterns in papillary thyroid cancer.

Ultrasonographic microcalcification is highly related to papillary thyroid cancer (PTC) and pathologic psammoma body is a poor prognostic factor. However, it is little known about whether the microcalcifications seen on ultrasonography are consistent with the pathologic psammoma bodies. We evaluated the relationship between ultrasonographic (US) calcification types and pathologic calcification features, and the consistency between observed pathologic and US calcifications.US calcifications were classified into microcalcification (MC) and nonmicrocalcification (non-MC) types, and pathologic calcifications were classified into 3 types: psammoma bodies, stromal calcifications, and ossifications.Among the 411 nodules that were reviewed by a pathologist, 38.9% (n = 160) had any type of US calcification. The larger the size of pathologic calcification, the more calcification was present in US (psammoma 46.1% < stromal 53.7% < ossification 73.3%). Psammoma bodies occurred in all US MC type. Ossification nodules occurred in nearly all (92.3%) non-MC type. The stromal-only nodules were 36.8% MC-type and 63.2% non-MC type. MC-type had a significantly higher odds ratio than non-MC type for predicting psammoma bodies according to the logistic regression.The presence of MC in ultrasonography was consistent with the presence of psammoma bodies. This study suggests that US identification of MC may be a useful prognostic indicator of PTC aggressiveness.

Excessive Iodine Status among School-Age Children in Korea: A First Report.

BACKGROUND: Korea is considered an iodine sufficient country, and several studies have been conducted regarding iodine status in healthy Korean adults, pregnant women, and preschool children. However, data on iodine status in Korean school-age children are lacking. Therefore, the iodine nutrition status of Korean school-age children was investigated by measuring urine iodine concentration (UIC). METHODS: This cross-sectional study conducted between April and September 2016 comprised 373 school-age children. UIC was determined using a modified microplate method employing ammonium persulfate digestion followed by Sandell-Kolthoff reaction. RESULTS: The median UIC was 458.2 µg/L. Excessive iodine intake (>300 µg/L) was found in 286 children (76.7%), with extremely high values exceeding 1,000 µg/L in 19.6% of subjects. Insufficient iodine intake (<100 µg/L) was observed in eight children (2.1%). UIC values were not significantly different between sexes. CONCLUSION: Korean school-age children showed excessive iodine intake. Therefore, education regarding adequate iodine intake in school-age children is needed.

Optimal glycemic target level for colon cancer patients with diabetes.

AIMS: The aim of this study was to evaluate the differences in mortality among colon cancer patients with or without diabetes and to determine optimal glycemic target level for colon cancer patients with diabetes. METHODS: A total of 741 patients with colon cancer between April 1999 and December 2010 were reviewed. The non-diabetes group had a fasting plasma glucose <126mg/dL, and the diabetes group had a fasting plasma glucose ⩾126mg/dL. Patients with diabetes were further divided based on glycemic control into either the uncontrolled subgroup (HbA1c ⩾8%) or the well-controlled subgroup (HbA1c <8%). RESULTS: Patients with diabetes had significantly shorter overall survival and median survival than non-diabetes patients. Uncontrolled diabetes patients had significantly shorter overall survival and median survival than well-controlled diabetes patients. The relative risk of mortality for diabetes patients was higher than non-diabetes patients (relative risk 1.17). The relative risk of mortality in uncontrolled diabetes patients was significantly higher than in well-controlled diabetes patients (relative risk 4.58). The area under the curve for mortality and HbA1c level was 0.73. The cut off HbA1c level was 7.75%. CONCLUSIONS: A optimal glycemic control level for colon cancer patients with diabetes should be recommended as an HbA1c of 7.8% or below.

Obesity and Hyperglycemia in Korean Men with Klinefelter Syndrome: The Korean Endocrine Society Registry.

BACKGROUND: The aim of this study was to investigate the prevalence of obesity in Korean men with Klinefelter syndrome (KS) and the associated risk factors for obesity and hyperglycemia. METHODS: Data were collected retrospectively from medical records from 11 university hospitals in Korea between 1994 and 2014. Subjects aged ≥18 years with newly diagnosed KS were enrolled. The following parameters were recorded at baseline before treatment: chief complaint, height, weight, fasting glucose level, lipid panel, blood pressure, testosterone, luteinizing hormone, follicle-stimulating hormone, karyotyping patterns, and history of hypertension, diabetes, and dyslipidemia. RESULTS: Data were analyzed from 376 of 544 initially enrolled patients. The rate of the 47 XXY chromosomal pattern was 94.1%. The prevalence of obesity (body mass index ≥25 kg/m²) in Korean men with KS was 42.6%. The testosterone level was an independent risk factor for obesity and hyperglycemia. CONCLUSION: Obesity is common in Korean men with KS. Hypogonadism in patients with KS was associated with obesity and hyperglycemia.

Serum 25-Hydroxyvitamin D Concentration Is Independently Inversely Associated with Insulin Resistance in the Healthy, Non-Obese Korean Population.

BACKGROUND: We evaluated the associations between 25-hydroxyvitamin D (25(OH)D) concentrations in serum and insulin resistance in the healthy Korean population. METHODS: We conducted this cross-sectional analysis in 1,807 healthy Korean people (628 men and 1,179 women) aged 30 to 64 years in the Cardiovascular and Metabolic Disease Etiologic Research Center study. All participants were assessed for 25(OH)D, fasting glucose, and insulin levels, and completed a health examination and lifestyle questionnaire according to standard procedures. Insulin resistance was defined as the homeostasis model assessment insulin resistance higher than the 75 percentile. RESULTS: Compared to those in the highest tertile (≥14.3 ng/mL), the odds ratio (OR) for insulin resistance was 1.37 (95% confidence interval [CI], 1.01 to 1.86) for the 1st tertile (<9.7 ng/mL) and 1.19 (95% CI, 0.08 to 1.62) for the 2nd tertile (9.7 to 14.3 ng/mL) after adjusting for age, gender, waist circumference, alcohol consumption, smoking status, physical exercise, season, and cohort. After stratification of the subjects by adiposity, these associations remained only in non-obese subjects (lowest tertile vs. highest tertile, multivariable OR, 1.64; 95% CI, 1.05 to 2.56). CONCLUSION: Serum 25(OH)D has an independent inverse association with insulin resistance in the healthy, non-obese Korean population, even among people with vitamin D insufficiency.

Application of New Cholesterol Guidelines to the Korean Adult Diabetic Patients.

The American College of Cardiology and the American Heart Association (ACC/AHA) 2013 joint guidelines for the treatment of hypercholesterolemia expand the indications for statin therapy. This study was performed to estimate the numbers of diabetic patients indicated for statin therapy according to the Third Adult Treatment Panel (ATP-III) of the National Cholesterol Education Program guidelines and the new ACC/AHA guidelines in Korea. We analyzed the data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2010-2012. Patients with diabetes over 30 yr of age were analyzed by the two guidelines. Of the total 1,975 diabetic patients, only 377 (19.1%) were receiving drugs for dyslipidemia. Among 1,598 patients who had not taken any medications for dyslipidemia, 65.6% would be indicated for statin therapy according to the ATP-III guidelines. When we apply the new guidelines, 94.3% would be eligible for statin therapy. Among the total diabetic patients, the new guidelines, compared with the ATP-III guidelines, increase the number eligible for statin therapy from 53.1% to 76.2%. The new guidelines would increase the indication for statin therapy for most diabetic patients. At present, many diabetic patients do not receive appropriate statin therapy. Therefore efforts should be made to develop the Korean guidelines and to ensure that more diabetic patients receive appropriate statin therapy.

Current iodine nutrition status and awareness of iodine deficiency in tuguegarao, Philippines.

The Philippines is one of the countries where adequate iodine status has been achieved. However, iodine deficiency still remains an important public health problem in this country. In this study, we evaluated iodine nutrition status and investigated an awareness status of iodine deficiency targeting high school students of Tuguegarao, Philippines. A total of 260 students provided samples for urinary iodine analysis, among which 146 students completed thyroid volume measurement by ultrasonography and answering the questionnaires. The median urinary iodine level was 355.3 µg/L and only 3.8% of the students were in the range of iodine deficiency status according to the ICCIDD criteria. Although 62.3% of students answered that they can list problems resulting from iodine deficiency, a majority of students (70.5%) were unable to identify problems other than goiter. They did not appreciate that adequate iodine levels are important during pregnancy and for development of children. 33.6% of students answered that they did not use iodized salt and the biggest reason was that they did not find it necessary. Based on these results, we suggest that a future strategy should be focused on vulnerable groups to completely eliminate iodine deficiency, including women at their reproductive ages and during pregnancy.

Tumor-suppressive effect of a telomerase-derived peptide by inhibiting hypoxia-induced HIF-1α-VEGF signaling axis.

A reverse-transcriptase-subunit of telomerase (hTERT) derived peptide, GV1001, has been developed as a vaccine against various cancers. Previously, we have shown that GV1001 interacts with heat shock proteins (HSPs) and penetrates cell membranes to be localized in the cytoplasm. In this study, we have found that GV1001 lowered the level of intracellular and surface HSPs of various cancer cells. In hypoxic conditions, GV1001 treatment of cancer cells resulted in decreases of HSP90, HSP70, and HIF-1α. Subsequently, proliferation of cancer cells and synthesis of VEGF were significantly reduced by treatment using GV1001 in hypoxic conditions. In an experiment using a nude mouse xenograft model, GV1001 exerted a similar tumor suppressive effect, further confirming its anti-tumor efficacy. Higher apoptotic cell death, reduced proliferation of cells, and fewer blood vessels were observed in GV1001-treated tumors compared to control. In addition, significant reduction of Tie2+ CD11b+ monocytes, which were recruited by VEGF from tumor cells and play a critical role in angiogenesis, was observed in GV1001-treated tumors. Collectively, the results suggest that GV1001 possesses potential therapeutic efficacy in addition to its ability to induce anti-cancer immune responses by suppressing both HSP70 and HSP90.