Enhancement of mucosal innate and adaptive immunity following intranasal immunization of mice with a bovine adenoviral vector.

Introduction: Nonhuman adenoviral (AdV) gene delivery platforms have significant value due to their ability to elude preexisting AdV vector immunity in most individuals. Previously, we have demonstrated that intranasal (IN) immunization of mice with BAd-H5HA, a bovine AdV type 3 (BAdV3) vector expressing H5N1 influenza virus hemagglutinin (HA), resulted in enhanced humoral and cell-mediated immune responses. The BAd-H5HA IN immunization resulted in complete protection following the challenge with an antigenically distinct H5N1 virus compared to the mouse group similarly immunized with HAd-H5HA, a human AdV type 5 (HAdV5) vector expressing HA. Methods: Here, we attempted to determine the activation of innate immune responses in the lungs of mice inoculated intranasally with BAd-H5HA compared to the HAd-H5HA-inoculated group. Results: RNA-Seq analyses of the lung tissues revealed differential expression (DE) of genes involved in innate and adaptive immunity in animals immunized with BAd-H5HA. The top ten enhanced genes were verified by RT-PCR. Consistently, there were transient increases in the levels of cytokines (IL-1α, IL-1ß, IL-5, TNF- α, LIF, IL-17, G-CSF, MIP-1ß, MCP-1, MIP-2, and GM-CSF) and toll-like receptors in the lungs of the group inoculated with BAdV vectors compared to that of the HAdV vector group. Conclusion: These results demonstrate that the BAdV vectors induce enhanced innate and adaptive immunity-related factors compared to HAdV vectors in mice. Thus, the BAdV vector platform could be an excellent gene delivery system for recombinant vaccines and cancer immunotherapy.

Women's cancers in Sudan with a focus on cervical cancer: turmoil, geopolitics and opportunities.

Cancer is the leading cause of death worldwide and the second leading cause of death in Sudanese women. However, despite proven interventions for primary, secondary and tertiary prevention and the World Health Organization's call to action toward eliminating cervical cancer, there has been little progress in addressing the cervical cancer burden in Sudan. This short communication intends to shed light on the challenges facing women's cancers in Sudan, taking cervical cancer as an example. It also discusses the opportunities and suggests ways to improve the outcomes of women's cancers in Sudan. Sudan's government should urgently implement a broad public health strategy to improve outcomes for women with cancer. The cancer control plan should be aligned with international, evidence-based recommendations and adapted to local circumstances. It should strengthen health literacy, augment different health care interventions, including vaccination, committed screening programmes, early detection and proper diagnosis of symptomatic cases, a programmatic approach to active management and palliative care and ensure robust referral pathways. Policies are also needed in collaboration with the international community in addressing the cancer care needs of internally displaced and refugee women in Sudan. The strategy should consider overcoming the existing challenges and making the most opportunities available.

Advances and challenges of CAR T therapy and suitability of animal models (Review).

Chimeric antigen receptors (CARs) recently gained momentum in cancer treatment due to their ability to promote T-cell mediated responses to a specific tumor-associated antigen. CARs are part of the adoptive cell transfer (ACT) strategies that utilize patients' T lymphocytes, genetically engineered to kill cancer cells. However, despite the therapy's success against blood-related malignancies, treating solid tumors has not reached its fullest potential yet. The reasons include the complex suppressive tumor microenvironment, mutations on cancer cells' target receptors, lethal side-effects, restricted trafficking into the tumor, suboptimal persistence in vivo and the lack of animal models that faithfully resemble human tumor's immunological responses. Currently, rodent models are used to investigate the safety and efficacy of CAR therapies. However, these models are limited in representing the human disease faithfully, fail to predict the adverse treatment events and overestimate the efficacy of the therapy. On the other hand, spontaneously developed tumors in dogs are more suited in CAR research and their efficacy has been demonstrated in a number of diseases, including lymphoma, osteosarcoma and mammary tumors. The present review discusses the design and evolution of CARs, challenges of CAR in solid tumors, human and canine clinical trials and advantages of the canine model.

Cancer in sub-Saharan Africa: a Lancet Oncology Commission.

In sub-Saharan Africa (SSA), urgent action is needed to curb a growing crisis in cancer incidence and mortality. Without rapid interventions, data estimates show a major increase in cancer mortality from 520 348 in 2020 to about 1 million deaths per year by 2030. Here, we detail the state of cancer in SSA, recommend key actions on the basis of analysis, and highlight case studies and successful models that can be emulated, adapted, or improved across the region to reduce the growing cancer crises. Recommended actions begin with the need to develop or update national cancer control plans in each country. Plans must include childhood cancer plans, managing comorbidities such as HIV and malnutrition, a reliable and predictable supply of medication, and the provision of psychosocial, supportive, and palliative care. Plans should also engage traditional, complementary, and alternative medical practices employed by more than 80% of SSA populations and pathways to reduce missed diagnoses and late referrals. More substantial investment is needed in developing cancer registries and cancer diagnostics for core cancer tests. We show that investments in, and increased adoption of, some approaches used during the COVID-19 pandemic, such as hypofractionated radiotherapy and telehealth, can substantially increase access to cancer care in Africa, accelerate cancer prevention and control efforts, increase survival, and save billions of US dollars over the next decade. The involvement of African First Ladies in cancer prevention efforts represents one practical approach that should be amplified across SSA. Moreover, investments in workforce training are crucial to prevent millions of avoidable deaths by 2030. We present a framework that can be used to strategically plan cancer research enhancement in SSA, with investments in research that can produce a return on investment and help drive policy and effective collaborations. Expansion of universal health coverage to incorporate cancer into essential benefits packages is also vital. Implementation of the recommended actions in this Commission will be crucial for reducing the growing cancer crises in SSA and achieving political commitments to the UN Sustainable Development Goals to reduce premature mortality from non-communicable diseases by a third by 2030.

Erratum: Prostate cancer clinical characteristics and outcomes in Central Sudan.

[This corrects the article on p. 1 in vol. 14.].

Prostate cancer clinical characteristics and outcomes in Central Sudan.

BACKGROUND: Prostate cancer is the most common cancer among Sudanese men and most patients present at a late stage. Although the incidence of prostate cancer in Sudan is low compared to other African countries, studies on prostate cancer in Sudan are limited. This study addresses the clinical characteristics and outcomes of prostate cancer in Central Sudan and its prognostic factors. METHODOLOGY: This study was conducted prospectively at the Gezira Hospital for Renal Disease and Surgery and at the National Cancer Institute at the University of Gezira, Sudan, for an 11-year period. RESULTS: During the study period, 543 patients participated in the study. Each one underwent a clinical examination, digital rectal examination and radiological staging using magnetic resonance imaging or computed tomography and provided blood samples for prostate-specific antigen (PSA) testing. The mean (SD) age of patients was 72.6 (9.9) years. At diagnosis, the majority of patients experienced lower urinary tract symptoms (LUTS; 54%), bladder outlet obstructions (OU) without (18%) or with urine retention (14%), PSA median was 100 ng/mL and the mean was 269 ng/mL, locally advanced disease (45%) or distant metastasis (46%). The age-adjusted hazard ratio (HR) of mortality was twofold, comparing patients presented with OU to patients with LUTS. Patients diagnosed with locally advanced and castration resistance prostate cancer had five times the HR compared to patients diagnosed with organ-confined prostate. On the contrary, the HR increased sevenfold for patients with distant metastasis. Gleason score did not show a significant association with survival (p = 0.249). Similarly, there was no apparent dose-response association between the PSA levels at diagnosis (p = 0.460). CONCLUSION: The findings suggest that Sudanese men who are living in Central Sudan present at diagnosis with large tumours at late stages, and high PSA levels and Gleason scores. Improving awareness and building up the treatment capacity are key to achieving better outcomes.

Partnerships and Collaborations: The Right Alliances for Clinical Trials in Africa.

Africa attracts < 1% of all trials conducted around the world. The implication is that proof of safety and efficacy in Africans is lacking for a lot of new therapies. The sizeable proportion of approximately 20% of the global population that Africa represents largely does not have empiric data to support use of new therapies in a population with a distinct genetic and racial profile. Beyond the imperative of evidence-based interventions, Africans carry a disproportionately heavy burden of certain diseases, including prostate cancer, sickle cell anemia, and malaria. It therefore provides opportunity for efficient recruitment of participants for trials for such diseases. However, this advantage has not convinced sponsors to carry out clinical trials in Africa. India and China each have roughly the same population size as Africa, but each presents just one regulatory jurisdiction for clinical trials. Africa has 54 countries, and a sponsor would theoretically need to file 54 different applications to cover the entire continent. Collaboration and partnership among all stakeholders in the clinical trial ecosystem will reduce the burden on sponsors and make Africa competitive as a destination for clinical trials. Collaboration among national regulatory agencies will enable Africa to be treated as one regulatory jurisdiction and reduce administrative burden. Sites and researchers can partner to improve quality, attain necessary certifications, and increase overall efficiency. Central to all of these are clinical research organizations that can coordinate and work across borders to make clinical trial projects seamless. Ultimately, patients will benefit as quality of clinical practice improves and access to new therapies is enhanced.

Tumor-Draining Lymph Secretome En Route to the Regional Lymph Node in Breast Cancer Metastasis.

BACKGROUND: During metastasis, tumor cells metastasize from primary tumors to distant organs via the circulatory and the lymphatic systems. There is a plethora of information about metastasis through the circulatory system, however not much information is available about the tumor cells dissemination through the lymphatic system or the lymphatic microenvironment that aids in this process in breast cancer metastasis. PURPOSE: The study designed to examine the tumor-derived secretome in lymph before reaching the draining lymph nodes. METHODS: Using a microsurgical technique, we have collected the lymph in transit from the primary tumor en route to the regional lymph node in animals with metastatic and non-metastatic mammary carcinoma and healthy controls. The lymph samples were subjected to LC-MS/MS analysis, bioinformatics, and pathway analysis. RESULTS: The metastatic tumor-draining lymph before its entry into the closest regional lymph node contain 26 proteins with >175-folds in abundance compared to lymph from non-metastatic tumor-bearing animals. Among these proteins were biliverdin reductase B, heat shock protein, coagulation factor XIII, lymphocytes cytosol protein 1, and aldose reductase. These proteins were not identified in the lymph from healthy animals. Pathways analysis revealed that cadherin-mediated endocytosis, acute phase response, junction signaling, gap junction, VEGF singling, and PI3K/AKT singling pathways are overrepresented in the lymph from metastatic tumor-bearing compared to the lymph from non-metastatic tumor-bearing animals. Among the significantly up-regulated proteins in the lymph from metastatic tumor-bearing animals were proteins that identified in exosomes include heat shock protein, enolase 1 alpha, S100, and biliverdin reductase B. One of the proteins significantly down-regulated in lymph from animals with metastasis is Kininogen, a known metastasis inhibitor protein. CONCLUSION: Proteins and exosomal proteins in lymph draining a metastatic tumor are different from those in lymph draining non-metastatic tumors, and these proteins involved in pathways that regulate tumor cells migration and invasion.

Author Correction: DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer.

The mechanisms that drive ductal carcinoma in situ (DCIS) progression to invasive cancer are not clear. Studying DCIS progression in humans is challenging and not ethical, thus necessitating the characterization of an animal model that faithfully resembles human disease. We have characterized a canine model of spontaneous mammary DCIS and invasive cancer that shares histologic, molecular, and diagnostic imaging characteristics with DCIS and invasive cancer in women. The purpose of the study was to identify markers and altered signaling pathways that lead to invasive cancer and shed light on early molecular events in breast cancer progression and development. Transcriptomic studies along the continuum of cancer progression in the mammary gland from healthy, through atypical ductal hyperplasia (ADH), DCIS, and invasive carcinoma were performed using the canine model. Gene expression profiles of preinvasive DCIS lesions closely resemble those of invasive carcinoma. However, certain genes, such as SFRP2, FZD2, STK31, and LALBA, were over-expressed in DCIS compared to invasive cancer. The over-representation of myoepithelial markers, epithelial-mesenchymal transition (EMT), canonical Wnt signaling components, and other pathways induced by Wnt family members distinguishes DCIS from invasive. The information gained may help in stratifying DCIS as well as identify actionable targets for primary and tertiary prevention or targeted therapy.

DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer unresponsive to traditional receptor-targeted treatments, leading to a disproportionate number of deaths. Invasive breast cancer is believed to evolve from non-invasive ductal carcinoma in situ (DCIS). Detection of triple-negative DCIS (TN-DCIS) is challenging, therefore strategies to study molecular events governing progression of pre-invasive TN-DCIS to invasive TNBC are needed. Here, we study a canine TN-DCIS progression and investigate the DNA methylation landscape of normal breast tissue, atypical ductal hyperplasia (ADH), DCIS and invasive breast cancer. We report hypo- and hypermethylation of genes within functional categories related to cancer such as transcriptional regulation, apoptosis, signal transduction, and cell migration. DNA methylation changes associated with cancer-related genes become more pronounced at invasive breast cancer stage. Importantly, we identify invasive-only and DCIS-specific DNA methylation alterations that could potentially determine which lesions progress to invasive cancer and which could remain as pre-invasive DCIS. Changes in DNA methylation during TN-DCIS progression in this canine model correspond with gene expression patterns in human breast tissues. This study provides evidence for utilizing methylation status of gene candidates to define late-stage (DCIS and invasive), invasive stage only or DCIS stage only of TN-DCIS progression.

Lymph-circulating tumor cells show distinct properties to blood-circulating tumor cells and are efficient metastatic precursors.

The leading cause of breast cancer-associated death is metastasis. In 80% of solid tumors, metastasis via the lymphatic system precedes metastasis via the vascular system. However, the molecular properties of tumor cells as they exit the primary tumor into the afferent lymphatics en route to the sentinel lymph nodes (SLNs) are not yet known. Here, we developed an innovative technique that enables the collection of lymph and lymph-circulating tumor cells (LCTCs) en route to the SLN in an immunocompetent animal model of breast cancer metastasis. We found that the gene and protein expression profiles of LCTCs and blood-circulating tumor cells (BCTCs) as they exit the primary tumor are similar, but distinct from those of primary tumors and lymph node metastases (LNMs). LCTCs, but not BCTCs, exist in clusters, display a hybrid epithelial/mesenchymal phenotype and cancer stem cell-like properties, and are efficient metastatic precursors. These results demonstrate that tumor cells that metastasize through the lymphatic system are different from those spread by blood circulation. Understanding the relative contribution of these cells to overall peripheral blood-circulating tumor cells is important for cancer therapy. Whether these two types of cell occur in cancer patients remains to be determined.

Magnetic Focus Lateral Flow Sensor for Detection of Cervical Cancer Biomarkers.

We report on a magnetic focus lateral flow biosensor (mLFS) for ultrasensitive detection of protein biomarkers in a practical format. With valosin-containing protein as a target protein, we show that the developed mLFS concept could detect as low as 25 fg/mL with magnetic focus to enhance target capture efficiency to deliver a 106-fold improvement in sensitivity compared to that of conventional lateral flow (LF) systems. The conceptualized strategy utilizes a simple magnet placed beneath the three-dimensional printed LF device to concentrate the targets at the signal zone without any additional instrumentation. In addition, protein mixtures extracted from the tissue of cervical cancer patients was also utilized to validate the sensor. To investigate the effect of magnetic focus on sensitivity, surface-enhanced Raman spectroscopy and dark-field imaging was utilized to characterize the distribution and movement of Fe3O4 core-Au shell nanoprobes in a model LF strip. Our experiments show that the magnetic focus results in an increased interaction time between the magnetic probe-labeled targets and the capture antibody, yielding a higher capture efficiency, allowing for ultrasensitive detection of the target not possible before with LF. The proposed mLFS can be utilized to detect a range of trace protein biomarkers for early diagnosis and can be combined with diverse pretreatment and signal amplification steps to query complex samples.

LXR/RXR pathway signaling associated with triple-negative breast cancer in African American women.

BACKGROUND: Triple-negative breast cancer (TNBC) is more prevalent in African and African American (AA) women compared to European American (EA) women. African and AA women diagnosed with TNBC experience high frequencies of metastases and less favorable outcomes. Emerging evidence indicates that this disparity may in fact be the result of the uniquely aggressive biology of African and AA disease. PURPOSE: To understand the reasons for TNBC in AA aggressive biology, we designed the present study to examine the proteomic profiles of TNBC and luminal A (LA) breast cancer within and across patients' racial demographic groups in order to identify proteins or molecular pathways altered in TNBC that offer some explanation for its aggressiveness and potential targets for treatment. MATERIALS AND METHODS: Proteomic profiles of TNBC, LA tumors, and their adjacent normal tissues from AA and EA women were obtained using 2-dimensional gel electrophoresis and bioinformatics, and differentially expressed proteins were validated by Western blot and immunohistochemistry. Our data showed that a number of proteins have significantly altered in expression in LA tumors compared to TNBC, both within and across patients' racial demographic groups. The differentially overexpressed proteins in TNBC (compared to LA) of AA samples were distinct from those in TNBC (compared to LA) of EA women samples. Among the signaling pathways altered in AA TNBC compared to EA TNBC are innate immune signaling, calpain protease, and pyrimidine de novo synthesis pathways. Furthermore, liver LXR/RXR signaling pathway was altered between LA and TNBC in AA women and may be due to the deficiency of the CYP7B1 enzyme responsible for cholesterol degradation. CONCLUSION: These findings suggest that TNBC in AA women enriched in signaling pathways that are different from TNBC in EA women. Our study draws a link between LXR/RXR expression, cholesterol, obesity, and the TNBC in AA women.

Longevity of adenovirus vector immunity in mice and its implications for vaccine efficacy.

There is a high incidence of adenovirus (AdV) infection in humans due to the presence of more than 60 types of human adenoviruses (HAdVs). The majority of individuals are exposed to one or more HAdV types early in their lives, leading to the development of AdV type-specific neutralizing antibodies. Similarly, immunization or gene therapy with AdV vectors leads to immune responses to the AdV vector. This 'vector immunity' is a concern for AdV vector-based applications for vaccines or gene therapy, especially when the repeated administration of a vector is required. The objective of this investigation was to establish whether AdV neutralizing antibody titers decline sufficiently in a year to permit annual vaccination with the same AdV vector. Naïve or human adenoviral vector group C, type 5 (HAdV-C5)-primed mice were mock-inoculated (with PBS) or inoculated i.m. with 108 PFU of either HAd-GFP [HAdV-C5 vector expressing the green fluorescent protein (GFP)] to mimic the conditions for the first inoculation with an AdV vector-based vaccine. At 1, 3, 6, and 10 months post-HAd-GFP inoculation, naïve- or HAdV-primed animals were vaccinated i.m. with 108 PFU of HAd-H5HA [HAdV-C5 vector expressing hemagglutinin (HA) of H5N1 influenza virus]. There was a significant continual decrease in vector immunity titers with time, thereby leading to significant continual increases in the levels of HA-specific humoral and cell-mediated immune responses. In addition, significant improvement in protection efficacy against challenge with an antigenically heterologous H5N1 virus was observed in HAdV-primed animals at 6 months and onwards. These results indicate that the annual immunization with the same AdV vector may be effective due to a significant decline in vector immunity.

Metabolic profiles of triple-negative and luminal A breast cancer subtypes in African-American identify key metabolic differences.

Breast cancer, a heterogeneous disease with variable pathophysiology and biology, is classified into four major subtypes. While hormonal- and antibody-targeted therapies are effective in the patients with luminal and HER-2 subtypes, the patients with triple-negative breast cancer (TNBC) subtype do not benefit from these therapies. The incidence rates of TNBC subtype are higher in African-American women, and the evidence indicates that these women have worse prognosis compared to women of European descent. The reasons for this disparity remain unclear but are often attributed to TNBC biology. In this study, we performed metabolic analysis of breast tissues to identify how TNBC differs from luminal A breast cancer (LABC) subtypes within the African-American and Caucasian breast cancer patients, respectively. We used High-Resolution Magic Angle Spinning (HR-MAS) 1H Nuclear magnetic resonance (NMR) to perform the metabolomic analysis of breast cancer and adjacent normal tissues (total n=82 samples). TNBC and LABC subtypes in African American women exhibited different metabolic profiles. Metabolic profiles of these subtypes were also distinct from those revealed in Caucasian women. TNBC in African-American women expressed higher levels of glutathione, choline, and glutamine as well as profound metabolic alterations characterized by decreased mitochondrial respiration and increased glycolysis concomitant with decreased levels of ATP. TNBC in Caucasian women was associated with increased pyrimidine synthesis. These metabolic alterations could potentially be exploited as novel treatment targets for TNBC.

Changing global policy to deliver safe, equitable, and affordable care for women's cancers.

Breast and cervical cancer are major threats to the health of women globally, particularly in low-income and middle-income countries. Radical progress to close the global cancer divide for women requires not only evidence-based policy making, but also broad multisectoral collaboration that capitalises on recent progress in the associated domains of women's health and innovative public health approaches to cancer care and control. Such multisectoral collaboration can serve to build health systems for cancer, and more broadly for primary care, surgery, and pathology. This Series paper explores the global health and public policy landscapes that intersect with women's health and global cancer control, with new approaches to bringing policy to action. Cancer is a major global social and political priority, and women's cancers are not only a tractable socioeconomic policy target in themselves, but also an important Trojan horse to drive improved cancer control and care.

Point-of-care test for cervical cancer in LMICs.

Cervical cancer screening using Papanicolaou's smear test has been highly effective in reducing death from this disease. However, this test is unaffordable in low- and middle-income countries, and its complexity has limited wide-scale uptake. Alternative tests, such as visual inspection with acetic acid or Lugol's iodine and human papillomavirus DNA, are sub-optimal in terms of specificity and sensitivity, thus sensitive and affordable tests with high specificity for on-site reporting are needed. Using proteomics and bioinformatics, we have identified valosin-containing protein (VCP) as differentially expressed between normal specimens and those with cervical intra-epithelial neoplasia grade 2/3 (CIN2/CIN3+) or worse. VCP-specific immunohistochemical staining (validated by a point-of-care technology) provided sensitive (93%) and specific (88%) identification of CIN2/CIN3+ and may serve as a critical biomarker for cervical-cancer screening. Future efforts will focus on further refinements to enhance analytic sensitivity and specificity of our proposed test, as well as on prototype development.

Incidence and survival rates of ovarian cancer in low-income women in Sudan.

Ovarian cancer is the second most common gynecological cancer worldwide. Little is known about the disease in Sudan. The objective of the present study was to evaluate the incidence rate, age and stage at diagnosis, and median survival time of patients presenting at the National Cancer Institute-University of Gezira (NCI-UG), Sudan. Data were collected in a prospective study of women with ovarian cancer over a period of eleven years of follow-up (between 2000 and 2011). Descriptive statistics were used to summarize the distribution of the demographics of the sample. The direct method was used to compute the age-standardized rate (ASR) using data from the 1966 and 2000 World Standard Populations (WSPs). The Kaplan-Meier method was used to estimate survival functions and the median survival time. Log-rank tests were used to statistically compare between the survival functions. There were steady increases in ovarian cancer incidence rates between 2000 and 2009, with a slight decline noted in 2010 and 2011. The patients' age range was 9-90. The age-specific incidence rate increased greatly in women aged 55 years or older. The majority of the patients had stage III or IV disease. The annual ASR using WSPs 1966 and 2000 as standard populations were 3.3 and 3.7 per 100,000 women, respectively. The median survival time was 31 months (95% confidence interval, 19-43). The 5-year cumulative survival rate was 38%. In Sudan, ovarian cancer affects postmenopausal women, akin to what is reported in the developed world with high incidence rates. Presenting with advanced stage disease is the predominant factor that results in a short survival time for women.

A multi-targeted approach to suppress tumor-promoting inflammation.

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.