Nebivolol Sensitizes BT-474 Breast Cancer Cells to FGFR Inhibitors.

BACKGROUND/AIM: The fibroblast growth factor receptor (FGFR) signaling pathway is abnormally activated in human cancers, including breast cancer. Therefore, targeting the FGFR signaling pathway is a potent strategy to treat breast cancer. The purpose of this study was to find drugs that could increase sensitivity to FGFR inhibitor effects in BT-474 breast cancer cells, and to investigate the combined effects and underlying mechanisms of these combinations for BT-474 breast cancer cell survival. MATERIALS AND METHODS: Cell viability was measured by MTT assay. Protein expression was determined by western blot analysis. mRNA expression was detected by Real-time PCR. Drug synergy effect was determined by isobologram analysis. RESULTS: Nebivolol, a third generation ß1-blocker, synergistically increased the sensitivity of BT-474 breast cancer cells to the potent and selective FGFR inhibitors erdafitinib (JNJ-42756493) and AZD4547. A combination of nebivolol and erdafitinib markedly reduced AKT activation. Suppression of AKT activation using specific siRNA and a selective inhibitor further enhanced cell sensitivity to combined treatment with nebivolol and erdafitinib, whereas SC79, a potent activator of AKT, reduced cell sensitivity to nebivolol and erdafitinib. CONCLUSION: Enhanced sensitivity of BT-474 breast cancer cells to nebivolol and erdafitinib was probably associated with down-regulation of AKT activation. Combined treatment with nebivolol and erdafitinib is a promising strategy for breast cancer treatment.

TL-ADA: Transferable Loss-based Active Domain Adaptation.

The field of Active Domain Adaptation (ADA) has been investigating ways to close the performance gap between supervised and unsupervised learning settings. Previous ADA research has primarily focused on query selection, but there has been little examination of how to effectively train newly labeled target samples using both labeled source samples and unlabeled target samples. In this study, we present a novel Transferable Loss-based ADA (TL-ADA) framework. Our approach is inspired by loss-based query selection, which has shown promising results in active learning. However, directly applying loss-based query selection to the ADA scenario leads to a buildup of high-loss samples that do not contribute to the model due to transferability issues and low diversity. To address these challenges, we propose a transferable doubly nested loss, which incorporates target pseudo labels and a domain adversarial loss. Our TL-ADA framework trains the model sequentially, considering both the domain type (source/target) and the availability of labels (labeled/unlabeled). Additionally, we encourage the pseudo labels to have low self-entropy and diverse class distributions to improve their reliability. Experiments on several benchmark datasets demonstrate that our TL-ADA model outperforms previous ADA methods, and in-depth analysis supports the effectiveness of our proposed approach.

Temporal Association of Total Serum Cholesterol and Pancreatic Cancer Incidence.

Previous studies have suggested a "cholesterol-lowering effect" of preclinical pancreatic cancer, suggesting lower total cholesterol as a potential diagnostic marker. Leveraging repeated measurements of total cholesterol, this study aims to examine the temporal association of total cholesterol and pancreatic cancer incidence. We conducted a nested case-control study based on a Korean National Health Insurance Service−Health Screening Cohort, including 215 pancreatic cancer cases and 645 controls matched on age and sex. Conditional logistic regression was applied to estimate the odds ratio (OR) and 95% confidence interval (CI) for the associations of pancreatic cancer incidence with total cholesterol levels across different time windows over 11 years before pancreatic cancer diagnosis (recent, mid, distant). We found that, compared to participants with total cholesterol < 200 mg/dL in the recent 3 years prior to diagnosis, those having total cholesterol ≥ 240 mg/dL showed a significantly lower pancreatic cancer incidence (OR = 0.50 (0.27−0.93)). No significant association was found in relation to total cholesterol measured in the mid and distant past. When changes in total cholesterol over the three time periods were analyzed, compared with those with total cholesterol levels consistently below 240 mg/dL over the entire period, the OR of pancreatic cancer was 0.45 (0.20−1.03) for participants with recent-onset hypercholesterolemia, 1.89 (0.95−3.75) for recent-resolved hypercholesterolemia, and 0.71 (0.30−1.66) for consistent hypercholesterolemia. In conclusion, while high total cholesterol in the recent past may indicate a lower pancreatic cancer incidence, a recent decrease in total cholesterol may suggest an elevated incidence of pancreatic cancer.

Knockdown of NUPR1 Enhances the Sensitivity of Non-small-cell Lung Cancer Cells to Metformin by AKT Inhibition.

BACKGROUND/AIM: Metformin is a widely used drug for type 2 diabetes mellitus and has recently attracted broad attention for its therapeutic effects on many cancers. This study aimed to investigate the molecular mechanism of metformin's anticancer activity. MATERIALS AND METHODS: Cell viability was measured by MTT assay. Gene and protein expression levels were determined by reverse transcription-polymerase chain reaction and western blot analyses, respectively. RESULTS: Metformin and phenformin markedly induced NUPR1 expression in a dose- and time-dependent manner in H1299 non-small-cell lung cancer (NSCLC) cells. The silencing of NUPR1 in H1299 NSCLC cells enhanced cell sensitivity to metformin or ionizing radiation. Our previous report showed that metformin induces AKT serine/threonine kinase (AKT) activation in an activating transcription factor 4 (ATF4)-dependent manner and that the inhibition of AKT promotes cell sensitivity to metformin in H1299 NSCLC cells. Interestingly, ATF4-induced AKT activation in H1299 NSCLC cells treated with metformin was suppressed by the knockdown of NUPR1. CONCLUSION: Targeting NUPR1 could enhance the sensitivity of H1299 NSCLC cells to metformin by AKT inhibition.

Knockdown of YAP/TAZ sensitizes tamoxifen-resistant MCF7 breast cancer cells.

Although endocrine therapy with tamoxifen has improved survival in breast cancer patients, resistance to this therapy remains one of the major causes of breast cancer mortality. In the present study, we found that the expression level of YAP/TAZ in tamoxifen-resistant MCF7 (MCF7-TR) breast cancer cells was significantly increased compared with that in MCF7 cells. Knockdown of YAP/TAZ with siRNA sensitized MCF7-TR cells to tamoxifen. Furthermore, siRNA targeting PSAT1, a downstream effector of YAP/TAZ, enhanced sensitivity to tamoxifen in MCF7-TR cells. Additionally, mTORC1 activity and survivin expression were significantly decreased during cell death induced by combination treatment with YAP/TAZ or PSAT1 siRNA and tamoxifen. In conclusion, targeting the YAP/TAZ-PSAT1 axis could sensitize tamoxifen-resistant MCF7 breast cancer cells by modulating the mTORC1-survivin axis.

Early-life body mass index and risks of breast, endometrial, and ovarian cancers: a dose-response meta-analysis of prospective studies.

BACKGROUND: The evidence for the associations between early-life adiposity and female cancer risks is mixed. Little is known about the exact shape of the relationships and whether the associations are independent of adult adiposity. METHODS: We conducted dose-response meta-analyses of prospective studies to summarise the relationships of early-life body mass index (BMI) with breast, endometrial, and ovarian cancer risks. Pubmed and Embase were searched through June 2020 to identify relevant studies. Using random-effects models, the summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated per 5-kg/m2 increase in BMI at ages ≤ 25 years. A nonlinear dose-response meta-analysis was conducted using restricted cubic spline analysis. RESULTS: After screening 33,948 publications, 37 prospective studies were included in this analysis. The summary RRs associated with every 5-kg/m2 increase in early-life BMI were 0.84 (95% CI = 0.81-0.87) for breast, 1.40 (95% CI = 1.25-1.57) for endometrial, and 1.15 (95% CI = 1.07-1.23) for ovarian cancers. For breast cancer, the association remained statistically significant after adjustment for adult BMI (RR = 0.80, 95% CI = 0.73-0.87). For premenopausal breast, endometrial, and ovarian cancers, the dose-response curves suggested evidence of nonlinearity. CONCLUSIONS: With early-life adiposity, our data support an inverse association with breast cancer and positive associations with ovarian and endometrial cancer risks.

Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis.

Amino acid availability is sensed by various signaling molecules, including general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). However, it is unclear how these sensors are associated with cancer cell survival under low amino acid availability. In the present study, we investigated AKT activation in non-small cell lung cancer (NSCLC) cells deprived of each one of 20 amino acids. Among the 20 amino acids, deprivation of glutamine, arginine, methionine, and lysine induced AKT activation. AKT activation was induced by GCN2/ATF4/REDD1 axis-mediated mTORC2 activation under amino acid deprivation. In CRISPR-Cas9-mediated REDD1-knockout cells, AKT activation was not induced by amino acid deprivation, indicating that REDD1 plays a major role in AKT activation under amino acid deprivation. Knockout of REDD1 sensitized cells cultured under glutamine deprivation conditions to radiotherapy. Taken together, GCN2/ATF4/REDD1 axis induced by amino acid deprivation promotes cell survival signal, which might be a potential target for cancer therapy.

miR-3188 Enhances Sensitivity of Breast Cancer Cells to Ionizing Radiation by Down-regulating Rictor.

BACKGROUND/AIM: Rictor is an adaptor protein essential for mTORC2, which regulates cell growth and survival. The aim of this study was to identify microRNAs (miR) that down-regulate Rictor and investigate their function on breast cancer cell survival. MATERIALS AND METHODS: Trypan blue assay, MTT assay, polymerase chain reaction analysis, luciferase reporter assay and western blot analysis were carried out in breast cancer cell lines HCC1954, MDA-MB-231, SK-BR-3, and BT474. RESULTS: miR-3188 overexpression suppressed the expression of Rictor and inhibited cell viability in HCC1954 and MDA-MB-231, highly Rictor-expressing breast cancer cells. In addition, miR-3188 overexpression decreased the protein level of p-AKT at Ser473, a substrate of mTORC2. Moreover, miRNA-3188 overexpression sensitized breast cancer cells to ionizing radiation (IR) by down-regulating Rictor and p-AKT. CONCLUSION: miR-3188 enhances IR sensitivity by affecting the mTORC2/AKT signalling pathway by altering the expression of Rictor, which could be a promising therapeutic strategy for the future treatment of breast cancer.

Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by Metformin.

BACKGROUND: Although the major anticancer effect of metformin involves AMPK-dependent or AMPK-independent mTORC1 inhibition, the mechanisms of action are still not fully understood. METHODS: To investigate the molecular mechanisms underlying the effect of metformin on the mTORC1 inhibition, MTT assay, RT-PCR, and western blot analysis were performed. RESULTS: Metformin induced the expression of ATF4, REDD1, and Sestrin2 concomitant with its inhibition of mTORC1 activity. Treatment with REDD1 or Sestrin2 siRNA reversed the mTORC1 inhibition induced by metformin, indicating that REDD1 and Sestrin2 are important for the inhibition of mTORC1 triggered by metformin treatment. Moreover, REDD1- and Sestrin2-mediated mTORC1 inhibition in response to metformin was independent of AMPK activation. Additionally, lapatinib enhances cell sensitivity to metformin, and knockdown of REDD1 and Sestrin2 decreased cell sensitivity to metformin and lapatinib. CONCLUSIONS: ATF4-induced REDD1 and Sestrin2 expression in response to metformin plays an important role in mTORC1 inhibition independent of AMPK activation, and this signalling pathway could have therapeutic value.

Inhibition of AKT Enhances the Sensitivity of NSCLC Cells to Metformin.

BACKGROUND/AIM: Metformin is an antidiabetic drug that has been reported to have antitumor activity in many cancer types. This study investigated the molecular mechanisms underlying the antitumor effect of metformin. MATERIALS AND METHODS: We investigated the molecular mechanism of the antitumor effect of metformin alone and in combination with AKT serine/threonine kinase (AKT) inhibition via cell viability and western blot analyses. RESULTS: Notably, metformin increased the phosphorylation of AKT at serine 473 using protein array screening. Metformin-induced AKT activation was markedly suppressed by siRNA targeting activating transcription factor 4 (ATF4) but not AMP-activated protein kinase α. These results indicate that AKT activation by metformin was induced in an ATF4-dependent and AMPKα-independent manner. Treatment using metformin combined with MK-2206, an AKT inhibitor, or a siRNA for AKT markedly reduced the viability of cells compared with those cells treated with these agents alone. In addition, MK-2206 increased cell sensitivity to the combination of metformin with ionizing radiation or cisplatin. CONCLUSION: Inhibition of AKT can enhance the antitumor effect of metformin and would be a promising strategy to sensitize non-small-cell lung cancer to a combination of metformin with radiation or cisplatin.

Association between weight cycling and risk of kidney cancer: a prospective cohort study and meta-analysis of observational studies.

PURPOSE: Weight cycling is common in populations. However, it is unclear whether frequency and magnitude of weight cycling is associated with kidney cancer risk, independent of body mass index (BMI). METHODS: A prospective cohort study followed 85,562 participants from Health Professionals Follow-up Study and Nurses' Health Study (1992-2014). At baseline, participants reported frequency and magnitude of intentional weight loss in the past 4 years. Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We also conducted a meta-analysis of all available observational studies including our two cohorts. RESULTS: During 22 years of follow-up, we identified 441 kidney cancer cases. Compared with non-weight cyclers (no attempt of intentional weight loss), severe cyclers (≥ 3 times of intentional weight loss of ≥ 4.5 kg) were at increased kidney cancer risk after adjusting for BMI before weight cycling (pooled multivariable-adjusted HR, 1.78; 95% CI, 1.19, 2.66). Additional adjustment for attained BMI after weight cycling had minimal influence. There was a positive trend between weight cycling by frequency and magnitude and kidney cancer risk (P-trend = 0.01). Moreover, the observed positive association did not differ by subtypes of cyclers (e.g., adiposity status, weight-loss methods). In the meta-analysis, we found a strong positive association between weight cycling and kidney cancer risk (summary relative risk for weight cyclers vs. non-cyclers, 1.51; 95% CI, 1.16, 1.96; I2: 52.2%; 6 studies). CONCLUSION: Frequent substantial weight cycling was associated with increased risk of kidney cancer, independent of BMI. Our study suggests that weight cycling may be an important risk factor for kidney cancer.

Preparation and Characterization of Planar-Type ZnO Powder with High Aspect Ratio for Application in Ultraviolet- and Heat-Shield Cosmetics.

In this study, a [0001]-plane planar-type ZnO ceramic powder material with a high aspect ratio ranging from 20:1-50:1 is synthesized using the electrolyte collected from zinc air battery power generation. This high aspect ratio may be due to the Zn(OH)2-4 anion dissolved in the electrolyte. The obtained planar-type ZnO exhibits excellent formulation stability and applicability, even when formulated as a cosmetic with a single inorganic ingredient. Compared to commercial ZnO or TiO2 powders, relatively better protection against infrared and ultraviolet (UV) radiation is realized due to its asymmetric characteristics, with a width of approximately 1 µm and thickness of tens of nm. The synthesized planar-type ZnO is mixed with nanosized ZnO or TiO2 commercial powders and formulated into various combinations to achieve a high UV protection rate and heat-blocking effect. In particular, the addition of planar-type ZnO to nanosized TiO2 powders increases the heat-blocking effect, and improves the applicability and formulation stability of the cosmetic formulation, despite the decrease in turbidity. Among all the ceramic powder combinations examined in this study, the best UV protection rate and heat-blocking effect are obtained when the synthesized planar-type ZnO is mixed with microsized and nanosized TiO2.

Time trends of colorectal cancer incidence and associated lifestyle factors in South Korea.

Worldwide, South Korea had the second highest incidence rates of colorectal cancer (CRC) in 2018. To inform public health policy to prevent CRC, we aimed to identify major modifiable lifestyle factors underlying the alarming increase in CRC incidence. We obtained information on CRC statistics from the Korea National Cancer Incidence Database and on the distribution of dietary and lifestyle factors known to modify CRC risk from the Korea National Health and Nutrition Examination Survey. To examine time trends between 2001 and 2013, we calculated annual percent changes of CRC incidence rates and of prevalence of etiologic factors by sex and age. Across all sex and age groups, the most commonly diagnosed cancer was rectal cancer while the most rapidly increasing cancer was distal colon cancer. For the lifestyle factors examined, decreases in exercise were observed across all age groups of both sexes. Yet, obesity and alcoholic drinks appear more relevant CRC contributor to men, smoking to women aged 30-49 years, and processed meat intake to adults aged 30-49 years. The heterogeneous results suggest that dietary and lifestyle target to prevent CRC be tailored by sex and age.

Lysine is required for growth factor-induced mTORC1 activation.

Mechanistic target of rapamycincomplex 1 (mTORC1) integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activity is sensitive to changes in amino acid levels. Here, we investigated the effect of lysine on mTORC1 activity in non-small cell lung cancer (NSCLC) cells. Lysine deprivation suppressed mTORC1 activity and lysine replenishment restored the decreased mTORC1 activity in lysine-deprived cells. Supplementing growth factors, such as insulin growth factor-1 or insulin restored the decreased mTORC1 activity in serum-deprived cells. However, in serum/lysine-deprived cells, supplementing growth factors was not sufficient to restore mTORC1 activity, suggesting thatgrowth factors could not activate mTORC1 efficiently in the absence of lysine. General control nonderepressible 2 and AMP-activated protein kinase were involved in lysine deprivation-mediated inhibition of mTORC1. Taken together, these results suggest that lysine might play role in the regulation of mTORC1 activation in NSCLC cells.

Alcohol Consumption and the Risk of Prostate Cancer: A Dose-Response Meta-Analysis.

Alcohol is widely consumed and is known as a major risk factor for several types of cancers. Yet, it is unclear whether alcohol consumption is associated with the risk of prostate cancer (PCa) or not. We conducted linear and non-linear dose-response meta-analyses of cohort studies on alcohol consumption and PCa risk by types of alcohol (total, wine, beer, and liquor) and PCa (non-aggressive and aggressive). Pubmed and Embase were searched through April 2020 to identify relevant studies. Summary relative risk (RR) and 95% confidence interval (CI) were estimated using a random-effects model. For non-aggressive PCa, by alcohol type, the risk increased linearly with liquor (RR per 14 g/day intake (alcohol content in standard drink) being 1.04 (95% CI = 1.02-1.06, I2 = 0%, three studies) and non-linearly with beer (Pnon-linearity = 0.045, four studies), with increased risk observed in the lower range (RR = 1.03, 95% CI = 1.01-1.05; 14 g/day), with 1.05 (95% CI = 1.01-1.08) at 28 g/day. Wine was not significantly associated with the risk of non-aggressive PCa. For aggressive PCa, a non-linear relationship of diverse shapes was indicated for all types of alcohol in the sensitivity analysis. Compared to non-drinking, a significant positive association was more apparent at lower dose for liquor (RR = 1.12, 95% CI = 1.04-1.20 at 14 g/day; RR = 1.16, 95% CI = 1.03-1.31 at 28 g/day; Pnon-linearity = 0.005, three studies) but at higher doses for wine (RR = 1.02, 95% CI = 0.90-1.16 at 28 g/day, RR = 1.35, 95% CI = 1.08-1.67 at 56 g/day; Pnon-linearity = 0.01, four studies). In contrast, decreased risks were indicated at lower doses of beer (RR = 0.85, 95% CI = 0.79-0.92 at 14 g/day; RR = 0.79, 95% CI = 0.70-0.90 at 28 g/day, Pnon-linearity < 0.001, four studies). Total alcohol consumption was not associated with both types of PCa. In this study, we found heterogeneous associations between alcohol intake and PCa by types of alcohol and PCa.

Hypoxia Suppresses Cysteine Deprivation-induced Cell Death Via ATF4 Regulation in MDA-MB-231 Breast Cancer Cells.

BACKGROUND/AIM: Cancer cells are frequently exposed to microenvironmental stresses, including amino acid deprivation and hypoxia, which are often targeted for cancer therapy. Here, we examined the effect of hypoxia in cysteine-deprived breast cancer cells and the mechanism to counteract the hypoxia effect. MATERIALS AND METHODS: Cell death was determined by annexin V-FITC and propidium iodide staining. Expression of mRNAs and proteins was determined by reverse transcription polymerase chain reaction and western blot analysis, respectively. RESULTS: Cysteine deprivation or sulfasalazine, a potent inhibitor of cysteine/glutamate transporter, induced cell death by activating transcription factor 4 (ATF4) up-regulation. Hypoxia significantly suppressed cell death and ATF4 up-regulation induced by cysteine deprived conditions. In addition, tumor necrosis factor-related apoptosis-inducing ligand reversed the effect of hypoxia on cysteine deprived conditions. CONCLUSION: Prevention of hypoxia may be a means for augmenting the effect of amino acid deprivation as a strategy for cancer therapy.

Knock-down of PSAT1 Enhances Sensitivity of NSCLC Cells to Glutamine-limiting Conditions.

BACKGROUND/AIM: Phosphoserine aminotransferase 1 (PSAT1) is an enzyme implicated in serine biosynthesis, and its overexpression has been linked to cancer cell proliferation. Therefore, targeting PSAT1 is considered to be an anticancer strategy. MATERIALS AND METHODS: The viability of non-small cell lung cancer (NSCLC) cells was measured by MTT assay. Protein and mRNA expression were determined by western blot and reverse transcription polymerase chain reaction, respectively. RESULTS: Glutamine-limiting conditions were generated through glutamine deprivation or CB-839 treatment, which induced PSAT1 expression in NSCLC cells. PSAT1 expression induced by glutamine-limiting conditions was regulated by activating transcription factor 4. Knock-down of PSAT1 enhanced the sensitivity of NSCLC cells to glutamine-limiting conditions. Interestingly, ionizing radiation induced PSAT1 expression, and knocking down PSAT1 increased cell sensitivity to ionizing radiation. CONCLUSION: Inhibiting PSAT1 might aid in the treatment of lung cancer, and PSAT1 may be a therapeutic target for lung cancer.

pS6K1 as an efficacy marker of GnRH agonist with premenopausal breast cancer.

Estradiol is a key factor for tumorigenesis and prognosis of hormone receptor-positive breast cancer. Adipocytes are one source of estradiol in patients with breast cancer. Recent studies have shown that phosphorylated ribosomal protein S6 kinase-1 plays a critical role in adipogenesis. Therefore, estrogen depletion therapy might have beneficial effects in phosphorylated ribosomal protein S6 kinase-1-positive breast cancer. This study was conducted to evaluate the value of phosphorylated ribosomal protein S6 kinase-1 as a marker for gonadotropin-releasing hormone agonist treatment, a form of estrogen depletion therapy, for premenopausal patients with HR-positive, human epidermal growth factor receptor 2-negative breast cancer. We reviewed the medical records of 296 premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary invasive breast cancer treated between 2008 and 2015. Phosphorylated ribosomal protein S6 kinase-1 positivity was defined by immunohistochemical staining scores of 1+, 2+ and 3+, whereas a score of 0 was considered negative. Phosphorylated ribosomal protein S6 kinase-1-positive tumors were found in 74.0% of the patients. In the phosphorylated ribosomal protein S6 kinase-1-positive group, disease-free survival of patients treated with a gonadotropin-releasing hormone agonist was significantly longer than that of patients treated without a gonadotropin-releasing hormone agonist (mean 106.7 months vs mean 91.1 months, P = 0.018). Phosphorylated ribosomal protein S6 kinase-1 is a potential biomarker for predicting the efficacy of gonadotropin-releasing hormone agonist therapy in premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.

Coffee Intake and Obesity: A Meta-Analysis.

Many studies have explored the relationship between coffee-one of the most commonly consumed beverages today-and obesity. Despite inconsistent results, the relationship has not been systematically summarized. Thus, we conducted a meta-analysis by compiling data from 12 epidemiologic studies identified from PubMed and Embase through February 2019. The included studies assessed obesity by body mass index (BMI, a measure of overall adiposity) or waist circumference (WC, a measure of central adiposity); analyzed the measure as a continuous outcome or binary outcome. Using random effects model, weighted mean difference (WMD) and 95% confidence interval (CI) were obtained for continuous outcomes; summary relative risk (RR) and 95% CI for the highest vs. lowest categories of coffee intake were estimated for binary outcome. For BMI, WMD was -0.08 (95% CI -0.14, -0.02); RR was 1.49 (95% CI 0.97, 2.29). For WC, WMD was -0.27 (95% CI -0.51, -0.02) and RR was 1.07 (95% CI 0.84, 1.36). In subgroup analysis by sex, evidence for an inverse association was more evident in men, specifically for continuous outcome, with WMD -0.05 (95% CI -0.09, -0.02) for BMI and -0.21 (95% CI -0.35, -0.08) for WC. Our meta-analysis suggests that higher coffee intake might be modestly associated with reduced adiposity, particularly in men.