The evidence linking vitamin D deficiency with increased risk of cardiovascular disease (CVD) extends back to 1970s when case control studies showed lower circulating concentrations of 25-hydroxyvitamin D [25(OH)D] in myocardial infarction cases compared with controls, which was strengthened by the identification of a vitamin D receptor in cardiac muscle in 1980s. Cohort studies published in the 2000s provided stronger evidence (by measuring 25(OH)D concentrations before the onset of CVD) and confirmed the inverse association between circulating 25(OH)D concentrations and CVD risk. However, concerns remained about possible residual confounding as the reason for the inverse association. This stimulated the initiation of several large scale randomized controlled trials (RCTs) of vitamin D supplementation with CVD as a pre-specified outcome. Results from these studies have been combined with findings from earlier RCTs in a recent meta-analysis undertaken on behalf of the US Endocrine Society. In 14 RCTs with 80,547 participants aged 50-74 years, vitamin D supplementation did not protect against CVD when compared to placebo: risk ratio 1.00 (95 % confidence interval 0.93-1.08). This result did not vary by study quality (risk of bias), gender, calcium co-administration, vitamin D dose or trial setting (community or residential care). This finding is consistent with recent mendelian randomization studies which have not detected a beneficial effect associated with genetically predicted 25(OH)D in people with vitamin D deficiency. Overall, the current evidence indicates that vitamin D does not prevent CVD.

Dietary factors can significantly affect the development of gastric and colorectal cancers; however, observational findings on the impact of micronutrients and macronutrients on the risk of gastric and colorectal cancers are inconsistent. It is crucial to clarify these relationships to create nutritional recommendations for cancer prevention. A two-sample Mendelian randomization investigation was performed to examine the impact of circulating levels of 15 micronutrients (such as vitamin A, folate, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc), along with adjusted relative macronutrient intake (including protein, carbohydrate, sugar, and fat), on the risk of gastric and colorectal cancers. Genetically predicted relative protein intake is significantly associated with the risk of colorectal cancer (odds ratio [OR] 95% confidence interval [CI] = 0.41 [0.24, 0.69]; P = .0007). Evidence suggests that genetically predicted macronutrients, such as carbohydrate (OR 95% CI = 1.88 [1.13, 3.14]; P = .0154), and micronutrients, such as vitamin C (OR 95% CI = 0.81 [0.69-0.94]; P = .008) and vitamin B12 (OR 95% CI = 1.16 [1.04, 1.28]; P = .006), may also influence the risk of colorectal cancer. Evidence suggests that intake of sugar (OR 95% CI = 0.47 [0.24, 0.90]; P = .02), and vitamin C (OR 95% CI = 0.78 [0.62, 0.99]; P = .04) may influence the risk of gastric cancer. However, no significant associations were observed between other nutrients and gastrointestinal malignancy. Taken together, these findings suggest that the intake of protein, carbohydrate, sugar, vitamin C, and vitamin B12 may influence the risk of gastric and colorectal cancers. However, further in-depth studies are needed to confirm this.

The high incidence of recurrence and malignant transformation of colorectal adenoma (CRA) are current issues that need to be addressed in clinical practice. Canmei Formula (CMF) has shown promising results in the prevention and treatment, however, it lacks effective clinical data support and its mechanism of action is not fully elucidated.

The aim of this study is to evaluate the clinical efficacy and safety of CMF in preventing and treating CRA, and to explore its effective chemical components and pharmacological mechanisms.

A randomized controlled clinical trial was conducted, with patients diagnosed with CRA within 6 months as the study subjects. After randomization, the patients were divided into a treatment group (receiving CMF granules) or a control group (receiving berberine hydrochloride tablets). The one-year recurrence rate of CRA was used as the key efficacy indicator to assess the effectiveness of CMF in preventing and treating CRA. The chemical components of CMF were identified using the UFLC-Q-TOF-MS/MS combined system. Data mining and the wSDTNBI algorithm were combined to construct a differential expression gene (DEG) - CMF prediction target interaction network for CRA. The core targets of CMF in CRA prevention and treatment were identified through topological analysis, and validated using molecular docking and in vitro experiments.

During the period from October 1 2021 to December 31 2023, a total of 228 participants were included in the study. After block randomization, 114 patients were assigned to each group. In the treatment group, 98 patients completed follow-up examinations, with 16 patients (14.0%) exhibiting shedding, Adenoma recurrence was identified in 24 (24.5%) patients through colonoscopy. In the control group, 99 cases completed the follow-up examination, while 15 cases (13.2%) were lost to follow-up. There were 45 cases (45.5%) experienced recurrence of adenomas. During the follow-up period, no cases of colorectal cancer or severe adverse reactions were reported. UFLC-QTOF-MS/MS identification was combined with traditional Chinese medicine database mining to obtain 192 active chemical components of Canmei Formula. Using the wSDTNBI algorithm, 1044 prediction targets were predicted, and 3308 differentially expressed genes of CRA were extracted from the TCGA database. Network topology analysis and bioinformatics analysis were performed on 164 intersecting core targets. Molecular docking and qPCR analysis revealed that CMF downregulates angiotensin II type 1 receptor (AT1R) and regulated interleukin-8 (CXCL8) and matrix metalloproteinase 13 (MMP13) within the REN/Ang II/AT1R axis of the renin-angiotensin signaling pathway, thereby preventing and treating CRA.

This small-scale randomized controlled clinical trial showed that CMF granules can safely and effectively reduce the risk of CRA recurrence. CMF prevents and treats colorectal adenomas by modulating the renin-angiotensin signaling pathway and the inflammatory response.

In nutrition research, randomised controlled trials (RCTs) and cohort studies provide complementary evidence. This meta-epidemiological study aims to evaluate the agreement of effect estimates from individual nutrition RCTs and cohort studies investigating a highly similar research question and to investigate determinants of disagreement.

MEDLINE, Epistemonikos, and the Cochrane Database of Systematic Reviews were searched from January 2010 to September 2021. We matched individual RCTs to cohort studies based on population, intervention/exposure, comparator, and outcome (PI/ECO) characteristics. Two reviewers independently extracted study characteristics and effect estimates and rated the risk of bias using RoB2 and ROBINS-E. Agreement of matched RCTs/cohort studies was analysed by pooling ratio of risk ratios (RRR) and difference of (standardised) mean differences (DSMD).

We included 64 RCT/cohort study pairs with 4,136,837 participants. Regarding PI/ECO similarity, 20.3% pairs were "more or less identical", 71.9% "similar but not identical" and 7.8% "broadly similar". Most RCTs were classified as "low risk of bias" (26.6%) or with "some concerns" (65.6%); cohort studies were mostly rated with "some concerns" (46.6%) or "high risk of bias" (47.9%), driven by inadequate control of important confounding factors. Effect estimates across RCTs and cohort studies were in high agreement (RRR 1.00 (95% CI 0.91-1.10, n = 54); and DSMD - 0.26 (95% CI - 0.87-0.35, n = 7)). In meta-regression analyses exploring determinants of disagreements, risk-of-bias judgements tend to have had more influence on the effect estimate than "PI/ECO similarity" degree.

Effect estimates of nutrition RCTs and cohort studies were generally similar. Careful consideration and evaluation of PI/ECO characteristics and risk of bias is crucial for a trustworthy utilisation of evidence from RCTs and cohort studies.

Colorectal cancer (CRC) is the fourth leading cause of cancer death globally. CRC surveillance is a common indication for colonoscopy, representing a considerable burden for endoscopy services. Accurate identification of high-risk patients who would benefit from more intensive surveillance, as well as low-risk patients suitable for less frequent follow-up, could improve the effectiveness of surveillance protocols and resource use. Our aim was to identify and critically appraise published risk models for the occurrence of metachronous advanced colorectal neoplasia (ACN), defined here as CRC or advanced adenomas detected during surveillance colonoscopy.

We searched PubMed and EMBASE for primary research studies reporting the development and/or validation of multivariable models that predict metachronous ACN risk. Screening of studies for inclusion, data extraction, and risk of bias assessment were conducted by two researchers independently.

We identified nine studies describing nine risk models. Six models were internally validated and two were externally validated. No model underwent both internal and external validation. Good model discrimination (concordance index > 0.7) was reported for two models during internal validation and for one model during external validation. Calibration was acceptable when assessed (n = 4). Methodological limitations and a high risk of bias were observed for all studies.

Several published models predicting metachronous ACN risk showed some promise. However, adherence to methodological standards was limited, and only two models were externally validated. Head-to-head comparisons of existing models using populations independent from model development cohorts should be prioritized to identify models suitable for use in clinical practice.

Oxysterols are metabolites of cholesterol that regulate the homeostasis of cholesterol, fatty acids, and glucose. These metabolites are generated throughout the body, either enzymatically or from oxidative stress, and are detectable in peripheral circulation. We previously reported that circulating 27-hydroxycholesterol (27-OHC), an endogenous selective estrogen receptor modulator, may be a risk factor for colorectal adenomas. Here, in addition to 27-OHC, we report on four other circulating oxysterols: 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7ɑ-hydroxycholesterol, and 4β-hydroxycholesterol. Oxysterol concentrations were measured using liquid chromatography/mass spectrometry from fasting plasma collected at baseline from 1,246 participants of the Vitamin D/Calcium Polyp Prevention Study, a multicenter adenoma chemoprevention trial. To evaluate multiple oxysterols simultaneously, we used both log-linear regression and Bayesian kernel machine regression models developed for analyses of complex mixtures adjusted for potential confounding factors. Higher circulating 7ɑ-hydroxycholesterol was associated with higher adenoma risk (Bayesian kernel machine regression-based multivariable-adjusted risk ratios (RR; for the 75th vs. 25th percentile, 1.22; 95% credible interval, CI, 1.04-1.42). In contrast, higher circulating 4β-hydroxycholesterol was associated with lower risk of these polyps (RR, 0.84; 95% CI, 0.71-0.99). The positive association with advanced adenoma risk that we previously reported for circulating 27-OHC persisted when controlling for other oxysterols (RR, 1.26; 95% CI, 0.98-1.62), including among those with advanced adenomas at baseline (RR, 1.75; 95% CI, 1.01-3.06). Prevention Relevance: Circulating concentrations of multiple oxysterols measured at the time of an initial colorectal adenoma diagnosis may be risk factors for subsequent incidence of these lesions. Novel colorectal cancer prevention strategies may target oxysterol formation.

To evaluate the effect of vitamin D supplementation on cardiovascular outcomes.

After searching different databases, we retrieved and included randomized controlled trials on long-term supplementation of vitamin D (≥1-year intervention) and reporting cardiovascular outcomes. We calculated risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes.

Compared to the control group, the vitamin D group was not associated with a statistically significant decrease in the incidence of major adverse cardiovascular events (MACE) [risk ratio=0.99; 95% CI: 0.94-1.03]. We found no difference between the vitamin D group and the control group for the outcomes of incidences of myocardial infarction, heart failure, coronary revascularization, cardiovascular death, and all-cause mortality. The heterogeneity was low for all outcomes.

According to our meta-analysis, vitamin D supplementation did not reduce major adverse cardiovascular events, other cardiovascular parameters, and all-cause mortality.

The aim of this study is to investigate whether vitamin D, calcium, ferritin, and uric acids play a beneficial biomarker role in the prevention of colorectal cancer (CRC) risk.

The case-control design was employed, including 650 CRC cases and 650 controls aged 35 to 70 years, comprising both men and women. The study encompasses sociodemographic data, clinical information, radiological diagnoses, and biochemical measurements.

Statistically significant differences were observed between CRC and controls in terms of age, diagnostic radiology, tomography, positron emission tomography/computed tomography (PET/CT), colonoscopy, CRC awareness, risk factors, age, genetics, exposure to chemicals, inadequate nutrition, smoking, hookah and alcohol use. Significant differences were also identified in intestinal inflammations, obesity, processed foods (P < 0.001), abdominal pain and cramps, diarrhea, constipation, blood in stool, bloating (gas), irritable bowel, nausea/vomiting, anemia, stress, fatigue, weakness, and weight loss. Regarding biochemical parameters, statistically significant differences were found between CRC and controls in terms of hemoglobin, glycated hemoglobin (HbA1c), fasting blood glucose (FBG), vitamin D, neutrophil level, red blood cell (RBC), white blood cell (WBC), platelet level, platelet count, hematocrit, potassium, sodium (Na), calcium, creatinine, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), bilirubin, uric acid, iron (Fe), ferritin, C-reactive protein (CRP), total protein, systolic blood pressure (SBP), and diastolic blood pressure (DBP) parameters (P < 0.001). Multivariate stepwise regression analysis was performed to find the best risk factors for the diagnosis of CRC as the dependent variable. As a result of the analysis, intestinal inflammation (P < 0.001), nausea/vomiting (P < 0.001), stomach pain (P = 0.003), hookah-smoking (P = 0.034), uric acid (P < 0.001), bilirubin (P < 0.001), cigarette smoke exposure (P = 0.033), processed food consumption (P = 0.002), calcium levels (P = 0.029), vitamin D deficiency (P < 0.001), and ferritin (P < 0.001) levels were identified as significant determinants for CRC.

The current study demonstrated that vitamin D, calcium, ferritin, and uric acids play a beneficial biomarker role in reducing the risk of CRC prevention. The increase in CRC rates may be associated with lifestyle, environmental and hereditary factors, nutrition, alcohol consumption, hookah use, and cigarette smoking.

Colorectal Cancer (CRC) has been molecularly classified into several subtypes according to tumor, stromal, and immune components. Here, we investigated whether the preventive effect of vitamin D on CRC varies with subtypes defined by Vitamin D receptor (VDR) expression in tumors and their surrounding stroma, along with the association of somatic mutations in CRC.

In a population-based prospective study of 22,743 Japanese participants, VDR expression levels in tumors and their surrounding stroma were defined in 507 cases of newly diagnosed CRC using immunohistochemistry. Hazard ratios of CRC and its subtypes according to dietary vitamin D intake were estimated using multivariable Cox proportional hazards models.

Dietary vitamin D intake was not associated with CRC or its subtypes defined by VDR expression in tumors. However, an inverse association was observed for CRC with high VDR expression in the stroma (the highest tertile vs the lowest tertile: 0.46 [0.23-0.94], Ptrend = 0.03), but not for CRC with low VDR expression in the stroma (Pheterogeneity = 0.02). Furthermore, CRC with high VDR expression in the stroma had more somatic TP53 and BRAF mutations and fewer APC mutations than those with low VDR expression in the stroma.

This study provides the first evidence that the preventive effect of vitamin D on CRC depends on VDR expression in the stroma rather than in the tumors. CRC with high VDR expression in the stroma is likely to develop through a part of the serrated polyp pathway, which tends to occur with BRAF but not with APC mutations.

Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain.

To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing.

A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined "empiric supplementation" as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D.

The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D-containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity.

The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits.

Low vitamin D status is common and is associated with various common medical conditions.

To support the development of the Endocrine Society's Clinical Practice Guideline on Vitamin D for the Prevention of Disease.

We searched multiple databases for studies that addressed 14 clinical questions prioritized by the guideline panel. Of the 14 questions, 10 clinical questions assessed the effect of vitamin D vs no vitamin D in the general population throughout the lifespan, during pregnancy, and in adults with prediabetes; 1 question assessed dosing; and 3 questions addressed screening with serum 25-hydroxyvitamin D (25[OH]D). The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess certainty of evidence.

Electronic searches yielded 37 007 citations, from which we included 151 studies. In children and adolescents, low-certainty evidence suggested reduction in respiratory tract infections with empiric vitamin D. There was no significant effect on select outcomes in healthy adults aged 19 to 74 years with variable certainty of evidence. There was a very small reduction in mortality among adults older than 75 years with high certainty of evidence. In pregnant women, low-certainty evidence suggested possible benefit on various maternal, fetal, and neonatal outcomes. In adults with prediabetes, moderate certainty of evidence suggested reduction in the rate of progression to diabetes. Administration of high-dose intermittent vitamin D may increase falls, compared to lower-dose daily dosing. We did not identify trials on the benefits and harms of screening with serum 25(OH)D.

The evidence summarized in this systematic review addresses the benefits and harms of vitamin D for the prevention of disease. The guideline panel considered additional information about individuals' and providers' values and preferences and other important decisional and contextual factors to develop clinical recommendations.

The role of dietary vitamins and antioxidants in preventing colorectal cancer (CRC) is a significant area of research within nutritional oncology. However, the relationship between these nutrients and CRC prevention is complex and influenced by factors such as dosage, timing, and individual health status. This review aims to comprehensively analyze and synthesize the existing scientific literature on the potential role of dietary vitamins and antioxidants in preventing CRC. A comprehensive literature review was conducted by searching electronic databases to identify studies examining the prospected impacts of dietary vitamins and antioxidants on the prevention of CRC. According to the outcomes of this review, this research review shows a complex link between vitamins and CRC. While some vitamins such as B2, B6, and D seemed helpful, others such as A and E had mixed results. Vitamin C deficiency was even linked to worse outcomes in cancer patients. Overall, the studies suggest focusing on a balanced diet rich in various vitamins rather than relying solely on individual supplements to prevent CRC. On the other hand, the results of our review suggest that the relationship between antioxidant intake and CRC is more intricate than previously thought. Data from this review indicates that taking specific antioxidant supplements such as selenium and vitamin E does not seem to offer the same protection. This suggests that a balanced diet with a variety of antioxidants is more helpful than focusing on single supplements. While we did not observe a direct association, future studies could investigate how different types and combinations of antioxidants might influence CRC development. In conclusion, the present systematic review highlights the need for more research on the relationship between vitamins, antioxidants, and CRC. We need to understand how these nutrients affect both the survival of people with CRC and the prevention of the disease. This will help us determine the best ways to use vitamins and antioxidants in CRC management and prevention.

Colorectal cancer (CRC) is one of the most life-threatening neoplasias in terms of incidence and mortality worldwide. Vitamin D deficiency has been associated with an increased risk of CRC. 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active vitamin D metabolite, is a pleiotropic hormone that, through its binding to a transcription factor of the nuclear receptor superfamily, is a major regulator of the human genome. 1,25(OH)2D3 acts on colon carcinoma and stromal cells and displays tumor protective actions. Here, we review the variety of molecular mechanisms underlying the effects of 1,25(OH)2D3 in CRC, which affect multiple processes that are dysregulated during tumor initiation and progression. Additionally, we discuss the epidemiological data that associate vitamin D deficiency and CRC, and the most relevant randomized controlled trials of vitamin D3 supplementation conducted in both healthy individuals and CRC patients.

Claudins are a family of 27 proteins that have an important role in the formation of tight junctions. They also have an important function in ion exchange, cell mobility, and the epithelial-to-mesenchymal transition, the latter being very important in cancer invasion and metastasis. Therapeutic targeting of claudins has been investigated to improve cancer outcomes. Recent evidence shows improved outcomes when combining monoclonal antibodies against claudin 18.2 with chemotherapy for patients with gastroesophageal junction cancer. Currently, chimeric antigen receptor T-cells targeting claudin 18 are under investigation. In this review, we will discuss the major functions of claudins, their distribution in the normal as well as cancerous tissues, and their effect in cancer metastasis, with a special focus on the therapeutic targeting of claudins to improve cancer outcomes.

The role of vitamin D in the prevention of chronic diseases including cancer, has received a great deal of attention during the past few decades. The term "Cancer" represents multiple disease states with varying biological complexities. The strongest link between vitamin D and cancer is provided by ecological and studies like observational, in preclinical models. It is apparent that vitamin D exerts diverse biological responses in a tissue specific manner. Moreover, several human factors could affect bioactivity of vitamin D. The mechanism(s) underlying vitamin D initiated anti-carcinogenic effects are diverse and includes changes at the muti-system levels. The oncogenic environment could easily corrupt the traditional role of vitamin D or could ensure resistance to vitamin D mediated responses. Several researchers have identified gaps in our knowledge pertaining to the role of vitamin D in cancer. Further areas are identified to solidify the role of vitamin D in cancer control strategies.

Large-scale genetic studies are reliably identifying many risk factors for disease in the general population. Several of these genetic risk factors encode potential drug targets, and genetics has already helped to introduce targeted agents for some diseases, an example being lipid-lowering drugs to reduce the incidence of cardiovascular disease. Multiple drugs have been developed to treat cancers based on somatic mutations and genomics, but in stark contrast, there seems to be a reluctance to use germline genetic data to develop drugs to prevent malignancy, despite the large numbers of people who could benefit, the potential for lowering cancer rates, and the widespread current use of non-pharmaceutical measures to reduce cancer risk factors such as tobacco, alcohol, and infectious diseases. We argue that concerted efforts for cancer prevention based on genetics, including genes influenced by common polymorphisms that modulate cancer risk, are urgently needed. There are enormous, yet underutilized, opportunities to develop novel targeted agents for chemoprevention of cancer based on human germline genetics. Such efforts are likely to require the support of a dedicated funding program by national and international agencies. See related commentary by Winham and Sherman, p. 13.

Vitamin D supplementation has seen a sharp increase in the primary healthcare setting but its efficacy in decreasing the risk of cardiovascular and cerebrovascular events is yet to be reliably established. We aim to determine whether vitamin D supplementation can significantly impact the risk of cardiovascular and cerebrovascular events. An extensive literature search of PubMed, Embase, and Cochrane CENTRAL was conducted from inception till August 2023 to include all the articles comparing vitamin D and placebo. Cardiovascular and cerebrovascular outcomes were presented as risk ratios (RR) with 95% confidence intervals (CIs) and pooled using a random effects model. Thirty-six trials consisting of 493,389 participants were included in our analysis. Our pooled analysis demonstrated no significant difference between vitamin D supplementation and placebo for the risk of cardiovascular mortality (RR 1.01, 95% CI 0.94-1.08; P = 0.80), stroke or cerebrovascular events (RR 1.03, 95% CI 0.95-1.11; P = 0.48), myocardial infarction (MI) (RR 0.98, 95% CI 0.91-1.06; P = 0.65), cerebrovascular mortality (RR 1.00, 95% CI 0.68-1.46; P = 0.99), arrhythmias (RR 0.98, 95% CI 0.66-1.44; P = 0.90) and hemorrhagic or ischemic stroke. There was no significant heterogeneity between the studies in any analysis. There was no significant difference in the risk of cardiovascular and cerebrovascular outcomes with vitamin D supplementation or placebo. Additional large high-powered studies focused on high-risk and vitamin D-deficient populations are required to resolve the current discrepancy in the literature and provide a definitive conclusion to this end.

The onset of colorectal adenomas (CRAs) is significantly associated with colorectal cancer. The preventive effects of chemical drugs on the recurrence of CRAs have been evaluated in a large number of randomized controlled trials (RCTs). However, there are still uncertainties about the relative effectiveness of such chemical drugs.

We searched relevant RCTs published in six databases up to February 2023. The quality of the included studies was assessed by using the Cochrane risk of bias assessment tool and Review Manager 5.4. Pairwise comparison and network meta-analysis (NMA) were conducted using RStudio to compare the effects of chemical drugs on the recurrence of CRAs.

Forty-five high-quality RCTs were included. A total of 35 590 (test group: 20 822; control group: 14 768) subjects with a history of CRAs have been enrolled and randomized to receive placebo treatment or one of 24 interventions. Based on surface under the cumulative ranking values and NMA results, difluoromethylornithine (DFMO) + Sulindac significantly reduced the recurrence of CRAs, followed by berberine and nonsteroidal antiinflammatory drugs.

DFMO + Sulindac is more effective in reducing the recurrence of CRAs but has a high risk of adverse events. Considering drug safety, tolerance, and compliance, berberine has a brighter prospect of clinical development. However, further studies are needed to verify our findings.

According to the findings from observational studies and clinical trials assessing the effect of vitamin D supplements on cardiovascular diseases (CVDs), there are still contradictory results. This systematic review aimed to assess the effect of vitamin D supplements on CVDs considering cohort studies and clinical trials. Study Design: A systematic review.

MEDLINE/PubMed, Science Direct, Embase, and Cochrane Library databases were reviewed by two reviewers independently until 2022. The study effect is risk ratio (RR) and 95% confidence interval (CI) according to Mantel Haenszel's random-effects model. Then, Stata version 14 was used for statistical analysis.

In clinical trial studies, the incidence of CVDs among the vitamin D-consuming group was not significantly different from that in the placebo group (RR: 0.99, 95% CI: 0.95-1.03; P=0.77; I 2=0%). CVD mortality was also not significantly different between the two groups (RR: 0.97, 95% CI: 0.90-1.05; P=0.72; I2=0%). In cohort studies, circulating 25 (OH) D increased the risk of CVD incidence by 31% (RR: 1.31, 95% CI: 1.19-1.45) and CVD mortality by 37% (RR: 1.37, 95% CI: 1.17-1.61).

According to current evidence from clinical trials, vitamin D supplementation should not be recommended for CVD prevention. However, there is a direct association between vitamin D deficiency and the incidence of CVDs as well as its mortality. According to the results of clinical trial studies carrying higher levels of scientific evidence, it can be concluded that vitamin D supplementation does not exert a significant effect on the incidence, mortality, and reduction of CVDs.

Fat-soluble vitamins (vitamin A, D, E, and K) assume a pivotal role in maintaining human homeostasis by virtue of their enzymatic functions. The daily inclusion of these vitamins is imperative to the upkeep of various physiological processes including vision, bone health, immunity, and protection against oxidative stress. Current research highlights fat-soluble vitamins as potential therapeutics for human diseases, especially cancer. Fat-soluble vitamins exert their therapeutic effects through multiple pathways, including regulation of matrix metalloproteinases' (MMPs) expression and enzymatic activity. As MMPs have been reported to be involved in the pathology of various diseases, such as cancers, cardiovascular diseases, and neurological disorders, regulating the expression and/or activity of MMPs could be considered as a potent therapeutic strategy. Here, we summarize the properties of fat-soluble vitamins and their potential as promising candidates capable of effectively modulating MMPs through multiple pathways to treat human diseases.

Diet is a critical regulator for physiological metabolism and tissue homeostasis, with a close relation to health and disease. As an important organ for digestion and absorption, the intestine comes into direct contact with many dietary components. The rapid renewal of its mucosal epithelium depends on the continuous proliferation and differentiation of intestinal stem cells (ISCs). The function and metabolism of ISCs can be controlled by a variety of dietary patterns including calorie restriction, fasting, high-fat, ketogenic, and high-sugar diets, as well as different nutrients including vitamins, amino acids, dietary fibre, and probiotics. Therefore, dietary interventions targeting ISCs may make it possible to prevent and treat intestinal disorders such as colon cancer, inflammatory bowel disease, and radiation enteritis. This review summarised recent research on the role and mechanism of diet in regulating ISCs, and discussed the potential of dietary modulation for intestinal diseases.

Some observational studies and randomised controlled trials (RCTs) have reported an association between calcium supplementation and increased risk of cardiovascular disease. Previous meta-analyses on the topic, based on data from RCTs and observational studies, have contradictory findings. This meta-analysis was conducted to determine the difference in associated risks of calcium supplementation with cardiovascular disease and stroke in RCTs.

Relevant studies published from database inception to 6 August 2021 were sourced from PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials. Any RCTs focusing on the relationship between calcium supplementation and incidence of cardiovascular disease or stroke were included. Articles were screened independently by two authors, according to the PICO criteria, with disagreements resolved by a third author.

Twelve RCTs were included in the meta-analysis. Calcium supplementation was not associated with myocardial infarction, total stroke, heart failure admission, and all-cause/cardiovascular mortality. Subgroup analysis focusing on calcium monotherapy/calcium co-therapy with vitamin D, female sex, follow-up duration, and geographical region did not affect the findings.

Calcium supplementation was not associated with myocardial infarction, total stroke, heart failure admission, and cardiovascular/all-cause mortality. Further studies are required to examine and understand these associations.

The role of circulating 25-hydroxyvitamin D (25(OH)D) in the prevention of early-onset colorectal cancer (CRC) in young adults aged <50 years is uncertain. We evaluated the age-stratified associations (<50 vs ≥50 years) between circulating 25(OH)D levels and the risk of CRC in a large sample of Korean adults.

Our cohort study included 236,382 participants (mean age, 38.0 [standard deviation, 9.0] years) who underwent a comprehensive health examination, including measurement of serum 25(OH)D levels. Serum 25(OH)D levels were categorized as <10, 10 to 20, and ≥20 ng/mL. CRC, along with the histologic subtype, site, and invasiveness, was ascertained through linkage with the national cancer registry. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CRC according to the serum 25(OH)D status, with adjustment for potential confounders.

During the 1,393,741 person-years of follow-up (median, 6.5 years; interquartile range, 4.5-7.5 years), 341 participants developed CRC (incidence rate, 19.2 per 105 person-years). Among young individuals aged <50 years, serum 25(OH)D levels were inversely associated with the risk of incident CRC with HRs (95% CIs) of 0.61 (0.43-0.86) and 0.41 (0.27-0.63) for 25(OH)D 10 to 19 ng/mL and ≥20 ng/mL, respectively, with respect to the reference (<10 ng/mL) (P for trend <.001, time-dependent model). Significant associations were evident for adenocarcinoma, colon cancer, and invasive cancers. For those aged ≥50 years, associations were similar, although slightly attenuated compared with younger individuals.

Serum 25(OH)D levels may have beneficial associations with the risk of developing CRC for both early-onset and late-onset disease.

Colorectal cancer has a high incidence and mortality worldwide, with Westernized lifestyles and diet being significant contributing factors. Vitamin D and calcium have been known to reduce the incidence of colorectal cancer by affecting cell differentiation, proliferation, and apoptosis. Despite observational studies which have suggested that a higher serum vitamin D level can lower the risk of colorectal cancer and improve survival rates, no large-scale randomized controlled trials to establish these benefits have been conducted to date. Calcium intake has also been found to have a beneficial role in reducing the incidence and improving survival rates of colorectal cancer in several observational studies. Moreover, intervention studies have proved its effect in preventing colorectal adenomas. However, there are few intervention studies that have identified the relationship of vitamin D and calcium with colon cancer. To elucidate the impact of vitamin D and calcium supplementation on colorectal cancer, well-designed and large-scale randomized controlled trials are necessary in the future.

Prevention and treatment of colorectal adenoma (CRA) are great significant to reduce morbidity and mortality of colorectal cancer. Although there have been numerous studies on CRA recently, few publications utilized the bibliometrics to evaluate this field. The objective of current study was to provide a comprehensive analysis of the current state and frontier progress of CRA over the past 20 years.

The Web of Science Core Collection was utilized to extracted all studies of CRA during 2002-2022. Bibliometric tools including CiteSpace, VOSviewer, and the Online Analysis Platform of Literature Metrology were used for statistical analysis. CiteSpace and the Online Analysis Platform were used to evaluate the contributions of various countries/regions, institutions, authors, and journals in this field. Research hotspots and trends were identified through keywords and references analysis by VOSviewer and CiteSpace.

2,268 publications from 2002 to 2022 in total were identified. The number of global publications in this field has increased annually. The USA was the most productive country, contributing nearly 30% of global publications. But in recent years, China's publications grew rapidly and had the highest citation strength. The most productive institutions was the National Cancer Institute. Baron JA from the USA was the most productive and the one of most co-cited authors. Cancer Epidemiology Biomarkers & Prevention had the highest number of publications and Gastroenterology was the most co-cited journals. Analysis of keywords clusters showed that "mechanism/pathophysiology", "risk factors and prevention", "colonoscopy screening and treatment", "metabolism", and "microbiota" were the major frontier topics and the main research directions.

CRA publications have shown a gradual upward trend in recent years, most of which have been published by developed countries. Developing countries should further focus on CRA research and transnational cooperation with developed countries in the future, in order to better improve the situation of the increasing morbidity and mortality of CRC. Baron JA was the most outstanding researcher in this field. More attention should be devoted to "pathogenesis of CRA", "less invasive diagnostic methods", "chemoprevention", and "screening and risk prediction of CRA including gut microbiome and metabolism", which will be frontiers in the future.

The aim of the study was to evaluate the preventive effect of 13 drugs on colorectal cancer (CRC) and guide the clinical application of these drugs.

PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure were searched for randomized controlled trials (RCTs) and cohort studies. The Cochrane bias risk assessment tool and the Newcastle-Ottawa Scale quality evaluation tool were used to evaluate the quality of the included RCTs and cohort studies. The funnel plot was used to analyze publication bias. A network meta-analysis of the extracted data was conducted using Stata16.0 software.

A total of 57 studies (34 RCTs and 23 cohort studies) involving 82719 participants were included. The network meta-analysis revealed that the quality of the included studies was good; the funnel plot showed no obvious publication bias. The network meta-analysis showed that the preventive effect of 13 drugs on CRC was better than that of the placebo. Allopurinol (SUCRA: 97.2%) was found to have the best effect, followed by berberine (SUCRA: 89.9%), non-aspirin NSAIDs (SUCRA: 84.5%), statins (SUCRA: 66.5%), metformin (SUCRA: 66.3%), calcium (SUCRA: 48.9%), mesalazine (SUCRA: 44.5%), ursodeoxycholic acid (SUCRA: 42.6%), vitamin D (SUCRA: 41.4%), mercaptopurine (SUCRA: 39.4%), aspirin (SUCRA: 30.4%), folic acid (SUCRA: 24.9%), and eicosapentaenoic acid (SUCRA: 16.3%).

The preventive effect of allopurinol on CRC was better than that of the other 13 drugs. These results can help doctors and patients understand the preventative effects of these drugs more intuitively and provide an evidence-based basis for the clinical application of these drugs.

To evaluate the effect of vitamin D3 supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86-1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78-0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91-1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D3 therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D3 supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D3 did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Objective: Colorectal cancer (CRC) is a common cancer that cannot be detected at an early stage and is a major challenge in oncology research. Studies have shown that vitamin D3 has some anti-cancer and preventive effects on colorectal cancer, but the exact anti-cancer mechanism is not clear. We applied the relevant research methods of network pharmacology to speculate and validate the possible potential pharmacological mechanisms of vitamin D3 for the prevention of colorectal cancer, and to provide more theoretical support for the clinical anticancer effects of vitamin D3. Methods: The relevant targets for vitamin D3 and CRC were obtained from the database of drug and disease targets, respectively. The target of vitamin D3 and the target of colorectal cancer were taken to intersect to obtain common targets. Then, the PPI network was constructed. In addition, the pathways of drug-disease interactions were predicted by GO and KEGG enrichment analysis. Finally, the obtained results were verified to ensure the reliability of the experiments. Results: 51 targets of vitamin D3 for the prevention of colorectal cancer were obtained. The 10 core targets were obtained from the PPI network. The 10 core targets include: ALB, SRC, MMP9, PPARG, HSP90AA1, IGF1, EGFR, MAPK1, MAP2K1 and IGF1R. The core targets were further validated by molecular docking and animal experiments. The results suggest that vitamin D3 plays a key role in the prevention of CRC through core targets, PI3K-Akt pathway, HIF-1 pathway, and FoxO pathway. Conclusion: This study will provide more theoretical support for vitamin D3 to reduce the incidence of CRC and is important to explore more pharmacological effects of vitamin D3.

The impact of vitamin D supplementation on cardiovascular outcomes and mortality risk reduction remains unclear due to conflicting study findings.

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), published between 1983 and 2022, that reported the effect of vitamin D supplementation in adults versus placebo or no treatment on all-cause mortality (ACM), cardiovascular mortality (CVM), non-cardiovascular mortality (non-CVM), and cardiovascular morbidities. Only studies with a follow-up period longer than one year were included. The primary outcomes were ACM and CVM. Secondary outcomes were non-CVM, myocardial infarction, stroke, heart failure, and major or extended adverse cardiovascular events. Subgroup analyses were performed according to low-, fair- and good-quality RCTs.

Eighty RCTs were assessed, including 82,210 participants receiving vitamin D supplementation and 80,921 receiving placebo or no treatment. The participants' mean (SD) age was 66.1 (11.2) years, and 68.6% were female. Vitamin D supplementation was associated with a lower risk of ACM (OR: 0.95 [95%CI 0.91-0.99] p = 0.013), was close to statistical significance for a lower risk of non-CVM (OR: 0.94 [95%CI 0.87-1.00] p = 0.055), and was not statistically associated with a lower risk of any cardiovascular morbi-mortality outcome. Meta-analysis of low-quality RCTs showed no association with cardiovascular or non-cardiovascular morbi-mortality outcomes.

The emerging results of our meta-analysis present evidence that vitamin D supplementation appears to decrease the risk of ACM (especially convincing in the fair- and good-quality RCTs), while not showing a decrease in the specific cardiovascular morbidity and mortality risk. Thus, we conclude that further research is warranted in this area, with well-planned and executed studies as the basis for more robust recommendations.

Many nutritional supplements and pharmacological agents have been reported to show preventive effects on colorectal adenoma and colorectal cancer (CRC). We performed a network meta-analysis to summarize such evidence and assess the efficacy and safety of these agents.

We searched PubMed, Embase, and the Cochrane Library for studies published in English until October 31, 2021 that fit our inclusion criteria. We performed a systematic review and network meta-analysis to assess the comparative efficacy and safety of candidate agents (low-dose aspirin [Asp], high-dose Asp, cyclooxygenase-2 inhibitors [coxibs], calcium, vitamin D, folic acid, ursodeoxycholic acid [UDCA], estrogen, and progesterone, alone or in combination) for preventing colorectal adenoma and CRC. Cochrane risk-of-bias assessment tool was employed to evaluate the quality of each included study.

Thirty-two randomized controlled trials (278,694 participants) comparing 13 different interventions were included. Coxibs significantly reduced the risk of colorectal adenoma (risk ratio [RR]: 0.59, 95% confidence interval [CI]: 0.44-0.79, six trials involving 5486 participants), advanced adenoma (RR: 0.63, 95% CI: 0.43-0.92, four trials involving 4723 participants), and metachronous adenoma (RR: 0.58, 95% CI: 0.43-0.79, five trials involving 5258 participants) compared with placebo. Coxibs also significantly increased the risk of severe adverse events (RR: 1.29, 95% CI: 1.13-1.47, six trials involving 7109 participants). Other interventions, including Asp, folic acid, UDCA, vitamin D, and calcium, did not reduce the risk of colorectal adenoma in the general and high-risk populations compared with placebo.

Considering the balance between benefits and harms, regular use of coxibs for prevention of colorectal adenoma was not supported by the current evidence. Benefit of low-dose Asp for chemoprevention of colorectal adenoma still requires further evidence.

PROSPERO, No. CRD42022296376.

Variants in the vitamin D-binding protein (DBP) gene (GC) encode DBP isoforms that may affect vitamin D metabolism. However, whether these isoforms modify the effects of vitamin D3 and/or calcium supplementation on colorectal adenoma recurrence is unclear. We hypothesized that supplementation effects may be stronger among those with the DBP2 isoform (encoded by the rs4588*A allele), which is associated with vitamin D deficiency and modified the associations of circulating vitamin D with risk for colorectal neoplasms in observational studies.

To estimate supplemental vitamin D3 and/or calcium effects on colorectal adenoma recurrence according to 3 common DBP isoforms (DBP1s, DBP1f, DBP2) encoded by 2 missense variants: rs7041 (NG_012837.3:g.57904T>G NP_001191235.1:p.Asp432Glu) and rs4588 (NG_012837.3:g.57915C>A NP_001191235.1:p.Thr436Lys).

Secondary analysis of a randomized, double-blind, placebo-controlled clinical trial of 2259 participants with a recently diagnosed adenoma and no remaining polyps after complete colonoscopy in the US from July 1, 2004, to August 31, 2013. The current analyses were performed from August 12, 2019, to July 16, 2022.

Daily vitamin D3 (1000 IU), calcium (1200 mg), both, or placebo.

One or more adenomas diagnosed during 3 to 5 years of follow-up. Treatment effects were estimated according to DBP isoform as risk ratios (RRs) and 95% CIs using Poisson regression analysis.

Of the 2259 participants randomized (mean [SD] age, 58 [6.8] years; 1033 [64%] men), 1604 non-Hispanic White participants (chosen to avoid population stratification bias) were included in the analysis. Among those with the DBP2 isoform (rs4588*AC or AA), the RRs (95% CI) for adenoma recurrence were 0.84 (0.72-1.00) with vitamin D3 relative to no vitamin D3, 0.83 (95% CI, 0.70-0.99) with calcium relative to no calcium, and 0.76 (95% CI, 0.59-0.98) with both agents relative to neither agent. Conversely, among those without DBP2 (rs4588*CC), the corresponding values were 1.08 (95% CI, 0.93-1.26; P = .03 for interaction) with vitamin D3 relative to no vitamin D3, 0.98 (95% CI, 0.84-1.14; P = .37 for interaction) with calcium relative to no calcium, and 1.09 (0.88-1.36; P = .03 for interaction) with both agents relative to neither agent. Among DBP2 homozygotes (rs4588*AA), the RR for adenoma recurrence was 0.57 (95% CI, 0.31-1.08) with both agents relative to neither agent.

The findings of this secondary analysis of a randomized clinical trial suggest that individuals with the DBP2 isoform-encoding rs4588*A allele may particularly benefit from vitamin D3 and/or calcium supplementation for colorectal adenoma prevention.

ClinicalTrials.gov Identifier: NCT00153816.

Vitamin D supplements may only be beneficial for the prevention of osteoporotic fractures when administered with calcium and in individuals with low blood levels of 25(OH)D, but possible hazards of calcium supplements on CVD cannot be excluded.

We conducted a meta-analysis of all placebo-controlled randomized trials assessing the effects of calcium supplements alone or with vitamin D on CHD, stroke, and all-cause mortality.

A meta-analysis of 11 trials included 7 comparisons of calcium alone compared with control (n = 8634) and 6 comparisons of calcium plus vitamin D compared with control (n = 46,804). Aggregated study-level data were obtained from individual trials and combined using a fixed-effects meta-analysis. The main outcomes included MI, CHD death, any CHD, stroke, and all-cause mortality.

Among trials of calcium alone (mean daily dose 1 g), calcium was not significantly associated with any excess risk of MI (RR, 1.15; 95% CI: 0.88, 1.51; n = 219 events), CHD death (RR, 1.24; 95% CI: 0.89, 1.73; n = 142), any CHD (RR, 1.01; 95% CI: 0.75, 1.37; n = 177), or stroke (RR, 1.15; 95% CI, 0.90, 1.46, n = 275). Among 6 trials of combined treatment, supplementation with calcium plus vitamin D was not significantly associated with any excess risk of MI (RR, 1.09; 95% CI: 0.95, 1.25; n = 854), CHD death (RR, 1.04; 95% CI: 0.85, 1.27; n = 391), any CHD (RR, 1.05; 95% CI: 0.93, 1.19; n = 1061), or stroke (RR, 1.02; 95% CI: 0.89, 1.17; n = 885). Likewise, calcium alone, or with vitamin D had no significant associations with all-cause mortality.

This meta-analysis demonstrated that calcium supplements were not associated with any significant hazard for CHD, stroke, or all-cause mortality and excluded excess risks above 0.3%-0.5% per year for CHD or stroke. Further trials of calcium and vitamin D are required in individuals with low blood levels of 25(OH)D for the prevention of fracture and other disease outcomes.

Interest in vitamin D has increased within the scientific community due to the impact of osteoporosis in the aging population. Vitamin D receptors are present in many tissues and low vitamin D status has been associated with many diseases in observational studies. There was hope that enhanced vitamin D provision might help prevent and treat some widespread disorders. Some of these hopes have been refuted by the results of recent large and well-conducted randomized trials. This review provides an overview of the basic physiology of vitamin D and an update on the evidence base for its clinical applications.

Colorectal cancer (CRC) is currently considered one of the most common and lethal types of tumors. Nutrition is of notorious relevance, given its influence in CRC prevention and treatment. This systematic review aimed to revise and update the state of knowledge regarding the potential role of vitamin D and calcium as key factors involved in the prevention and treatment of CRC. A literature search was performed in PubMed and Web of Science. A total of eight studies were finally included in the present review. Vitamin D showed a protective role by promoting transcriptomic changes associated with antitumor effects. However, no significant effects of vitamin D were noted in the relapse-free survival of patients at 5 years. On the other hand, previous scientific evidence demonstrated that calcium regulates the expression of colonic proteins that decrease cell proliferation and increase cell differentiation. Nevertheless, an increased risk of associated serrated adenomas was found in response to calcium and calcium + vitamin D supplementation. Moreover, supplementation with both nutrients showed positive changes on relevant CRC biomarkers including TGFα, TGFβ1, APC, β-catenin and E-cadherin. In conclusion, vitamin D supplementation seems to have a protective effect in the prevention and treatment of CRC, while calcium intake showed contradictory effects as a prevention or treatment tool; therefore, further studies are necessary to well understand its relevance in patients with CRC.

Milk is related to many gastrointestinal disorders from the cradle to the grave due to the many milk ingredients that can trigger gastrointestinal discomfort and disorders. Cow's milk protein allergy (CMPA) is the most common food allergy, especially in infancy and childhood, which may persist into adulthood. There are three main types of CMPA; immunoglobulin E (IgE)-mediated CMPA, non-IgE-mediated CMPA, and mixed type. CMPA appears before the first birthday in almost all cases. Symptoms may start even during the neonatal period and can be severe enough to simulate neonatal sepsis. CMPA (often non-IgE mediated) can present with symptoms of gastroesophageal reflux, eosinophilic esophagitis, hemorrhagic gastritis, food protein-induced protein-losing enteropathy, and food protein-induced enterocolitis syndrome. Most CMPAs are benign and outgrown during childhood. CMPA is not as common in adults as in children, but when present, it is usually severe with a protracted course. Lactose intolerance is a prevalent condition characterized by the development of many symptoms related to the consumption of foods containing lactose. Lactose intolerance has four typical types: Developmental, congenital, primary, and secondary. Lactose intolerance and CMPA may be the underlying pathophysiologic mechanisms for many functional gastrointestinal disorders in children and adults. They are also common in inflammatory bowel diseases. Milk consumption may have preventive or promoter effects on cancer development. Milk may also become a source of microbial infection in humans, causing a wide array of diseases, and may help increase the prevalence of antimicrobial resistance. This editorial summarizes the common milk-related disorders and their symptoms from childhood to adulthood.

Previous randomized controlled trials (RCTs) and meta-analyses of RCTs evaluating vitamin D supplementation for the prevention of cancer incidence and mortality have found inconsistent results and no meta-analysis has assessed the quality of the evidence available. We, therefore, aimed to perform an updated meta-analysis by including recent large-scale RCTs and assessing the quality of the pooled evidence.

We searched several databases and trial registers from inception to April 2022. We used a random-effects model to estimate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We used the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) considerations to evaluate the certainty of evidence.

We included 13 RCTs in our study. Vitamin D supplementation had no effect on the risk of total cancer incidence (RR 0.99, 95% CI: 0.94-1.04; I 2 = 0%), total cancer mortality (RR 0.93, 95% CI: 0.84-1.03; I 2 = 24%) and total mortality (RR 0.92, 95% CI: 0.82-1.04; I 2 = 36%). The overall quality of evidence was high for all outcomes.

Vitamin D supplementation is ineffective in reducing total cancer incidence and mortality in largely vitamin D-replete older adult populations. Future research should be based on populations with a higher prevalence of vitamin D deficiency and should involve more extended follow-up periods.

PROSPERO database, CRD42021285401.