Comparison of Publications on Heated Tobacco Products With Conventional Cigarettes and Implied Desirability of the Products According to Tobacco Industry Affiliation: A Systematic Review.

INTRODUCTION: Heated tobacco products (HTPs) have been advertised as "reduced-harm" tobacco products compared to conventional cigarettes (CC); however, no direct evidence supporting HTPs being desirable for human health exists. A previous systematic review reported that evidence on HTPs published in 2017 or earlier was primarily drawn from industry-related papers. We aimed to investigate whether tobacco industry-affiliated studies are more likely to conclude that HTPs are more desirable than CC. METHODS: PubMed and Ichushi-Web were searched up to March 15, 2022, for studies on HTPs published in 2017 or after. We selected studies that assessed any measures of HTPs and CC, including secondary analyses using gray literature in English or Japanese. We excluded review articles except for a meta-analysis that met the aforementioned criteria. Data on the authors' affiliations, grant, conflict of interest, category of research subjects, and interpretation were extracted. Research members in two groups independently assessed the papers; discrepancies were solved by discussion between the groups. RESULTS: Overall, 134 studies met the criteria. Eighty-seven (64.9%) of them were affiliated with the tobacco industry. Of the 134 studies, 56.3% (49/87) of the industry-affiliated studies versus 19.1% (9/47) of nonindustry-affiliated studies concluded that HTPs were more desirable than CC (p < .01). No study investigated clinically relevant outcomes, such as disease occurrence. CONCLUSIONS: Publications on HTPs in the biomedical literature from January 2017 to March 2022 were dominated by tobacco industry-affiliated studies. More than half of them concluded that HTPs were more desirable than CC compared to independent studies. IMPLICATIONS: Tobacco industry advertises HTPs as "reduced-harm" tobacco products compared to CC. HTP users tend to consider HTPs as alternative tobacco products less harmful than CC (ie, products for "harm reduction"). Our results demonstrated that papers written by tobacco industry-affiliated authors concluded that HTPs were more desirable than CC compared to papers by independent authors. However, all their judgments were based on surrogate outcomes. Surrogate outcomes are not necessarily linked to clinically relevant outcomes such as disease occurrence. Further studies on HTPs using clinically relevant outcomes are warranted by independent authors from tobacco industry.

Potential hypotensive effects of Umezu polyphenols: a 14-week community-based, double-masked and placebo-controlled trial.

OBJECTIVE: To evaluate blood pressure (BP)-lowering effects of Umezu polyphenols, polyphenols contained in Japanese plums, in a community-based sample by double-masked and placebo-controlled design. METHODS: Seventy-two Japanese community-dwellers who were interested in prevention or control of their BP (preferably high-normal BP or grade I hypertension) but without antihypertensive medication were randomized into Umezu polyphenols or placebo groups. Each subject took 800 mg/day of Umezu polyphenols or placebo for 12 weeks, followed by a 2-week washout period. Their home and office BP were monitored for 14 weeks in a double-masked manner. We analyzed 56 subjects who met the inclusion criteria. RESULTS: Home BP increased gradually in both the groups during the intervention period, while diastolic office BP insignificantly decreased in the intervention group. During the washout period, home systolic BP in the morning elevated only in the intervention group. CONCLUSIONS: The study failed to collect consistent evidence of a clear persistent hypotensive effect of Umezu polyphenols.

EphA4-deleted microenvironment regulates cancer development and leukemoid reaction of the isografted 4T1 murine breast cancer via reduction of an IGF1 signal.

UNLABELLED: EphA4 belongs to the largest family of receptor tyrosine kinases (RTKs). Although EphA4 is highly expressed in the central nervous system, EphA4 has also been implicated in cancer progression. Most of the studies focus on the expression and function in tumor cells. It is unknown whether EphA4-deleted microenvironment affects tumor progression. Some of cancers in animals and humans, such as 4T1 cancer cells, are known to produce a large amount of granulocyte colony-stimulating factors (G-CSF/Csf3) which can stimulate myeloproliferation, such as myeloid-derived suppressor cells (MDSCs) leading to a poor recipient prognosis. We isografted 4T1 breast cancer cells into both EphA4-knockout and control wild-type female littermate mice. The results showed that the EphA4-deleted host could inhibit primary tumor growth and tumor metastasis mainly by decreasing the amount of IGF1 synthesis in the circulation and locally tissues. The EphA4-deleted microenvironment and delayed tumor development reduced the production of G-CSF resulting in the decrease of splenomegaly and leukemoid reaction including MDSCs, which in turn inhibit the tumor progression. This inhibition can be reversed by supplying the mice with IGF1. However, an excess of IGF1 supply over demand to the control mice could not further accelerate the tumor growth and metastasis. A better understanding and re-evaluation of the main role of IGF1 in regulating tumor progression could further enhance our cognition of the tumor development niche. Our findings demonstrated that EphA4-deleted microenvironment impairs tumor-supporting conditions. CONCLUSION: Host EphA4 expression regulates cancer development mainly via EphA4-mediated IGF1 synthesis signal. Thus, targeting this signaling pathway may provide a potential therapeutic option for cancer treatment.

Safety and adherence of Umezu polyphenols in the Japanese plum (Prunus mume) in a 12-week double-blind randomized placebo-controlled pilot trial to evaluate antihypertensive effects.

OBJECTIVES: Medications or lifestyle changes to prevent or improve hypertension often press considerable efforts on patients suffering from mild hypertension. Capsules including Umezu polyphenols (UP), polyphenols in Japanese plums, may help them to control their blood pressure (BP). The aim of this study is to evaluate the effectiveness of UP on BP and its safety. METHODS: A total of 15 healthy workers without antihypertensive medication who had some concerns about their BP, preferably normal-high BP or hypertension level 1, were randomized in a double-blind manner into UP ingesting and placebo groups. Each subject was instructed to take four capsules daily for 12 weeks (daily UP dose, 800 mg for the UP ingesting group; and 0 mg for the placebo group). These subjects were followed for 12 weeks, and their BP both at home and at the examination site, as well as self-perceived quality-of-life outcomes and possible side effects, was monitored during that period. Group × time interactions on BP changes were examined. RESULTS: All of the 15 subjects completed the 12-week intervention trial. The BP changes did not significantly differ between the UP ingesting and placebo groups, neither at the examination site nor at home. But during the study period, no adverse effects were observed. CONCLUSIONS: No remarkable effect of UP on BP was observed. However, a higher dose of UP was confirmed safe and high in adherence in this 12-week randomized controlled trial. Its effect on BP and other outcomes shall be confirmed in a larger sample.

Linking lifestyle factors and insulin resistance, based on fasting plasma insulin and HOMA-IR in middle-aged Japanese men: a cross-sectional study.

OBJECTIVE: Insulin resistance (IR) is regarded as one of the earliest features of many metabolic diseases, and major efforts are aimed at improving insulin function to confront this issue. The aim of this study was to investigate the relationship of body mass index (BMI), cigarette smoking, alcohol intake, physical activity, green tea and coffee consumption to IR. METHODS: We performed a cross-sectional study of 1542 male self defense officials. IR was defined as the highest quartile of the fasting plasma insulin (≥ 50 pmol/L) or the homeostasis model assessment-estimated IR (HOMA-IR ≥ 1.81). An unconditional logistic model was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between IR and influential factors. Stratified analysis by obesity status (BMI < 25 kg/m(2), non-obese; ≥ 25 kg/m(2), obese) was performed. RESULTS: IR was significantly positively related to BMI and glucose tolerance, negatively related to alcohol use. Independent of obesity status, significant trends were observed between IR and alcohol use. Drinking 30 mL or more of ethanol per day reduced IR by less than 40%. Strong physical activity was associated with decreased risk of IR based on fasting plasma insulin only in the obese. Coffee consumption was inversely associated with the risk of IR based on HOMA-IR in the non-obese group. CONCLUSION: Higher coffee consumption may be protective against IR among only the non-obese. Further studies are warranted to examine the effect modification of the obesity status on the coffee-IR association.

Predicting lymph node metastasis in early colorectal cancer using the CITED1 expression.

BACKGROUND: The identification of molecular markers that are useful for predicting lymph node metastasis is urgently needed to determine treatment strategies for T1 colorectal cancer (CRC). We previously showed that 10 candidate genes are correlated with de-differentiation at the invasion front of CRC using a gene expression analysis. These 10 genes are potential markers that may predict lymph node metastasis by CRC. MATERIALS AND METHODS: Samples were obtained from 161 patients with CRC. Quantitative real-time reverse transcription-polymerase chain reaction assays were performed using 66 T3 samples in order to extract genes correlated with lymph node metastasis. Immunohistochemical studies of the extracted genes were performed on 66 T3 and 95 T1 samples. A univariate analysis followed by a multivariate logistic regression model was used to examine independent risk factors for lymph node metastasis. RESULTS: The CITED1 messenger RNA expression was found to be an independent risk factor for lymph node metastasis in T3 CRC patients (P = 0.040). A high CITED1 protein expression, as detected with immunohistochemistry, was also an independent risk factor in T3 CRC patients (P = 0.035). In T1 colorectal cancer patients, a high CITED1 protein expression was found to be an independent risk factor for lymph node metastasis (P = 0.010). The positive predictive and negative predictive values in the T1 colorectal cancer patients were 27.5% and 95.5%, respectively. CONCLUSIONS: The CITED1 expression is correlated with lymph node metastasis in patients with CRC. In T1 colorectal cancer patients, CITED1 has the potential ability to predict the presence of lymph node metastasis.