Vibrational spectroscopy for decoding cancer microbiota interactions: Current evidence and future perspective.

The role of human microbiota in cancer initiation and progression is recognized in recent years. In order to investigate the interactions between cancer cells and microbes, a systematic analysis using various emerging techniques is required. Owing to the label-free, non-invasive and molecular fingerprinting characteristics, vibrational spectroscopy is uniquely suited to decode and understand the relationship and interactions between cancer and the microbiota at the molecular level. In this review, we first provide a quick overview of the fundamentals of vibrational spectroscopic techniques, namely Raman and infrared spectroscopy. Next, we discuss the emerging evidence underscoring utilities of these spectroscopic techniques to study cancer or microbes separately, and share our perspective on how vibrational spectroscopy can be employed at the intersection of the two fields. Finally, we envision the potential opportunities in exploiting vibrational spectroscopy not only in basic cancer-microbiome research but also in its clinical translation, and discuss the challenges in the bench to bedside translation.

Adiponectin, Obesity, and Cancer: Clash of the Bigwigs in Health and Disease.

Adiponectin is one of the most important adipocytokines secreted by adipocytes and is called a "guardian angel adipocytokine" owing to its unique biological functions. Adiponectin inversely correlates with body fat mass and visceral adiposity. Identified independently by four different research groups, adiponectin has multiple names; Acrp30, apM1, GBP28, and AdipoQ. Adiponectin mediates its biological functions via three known receptors, AdipoR1, AdipoR2, and T-cadherin, which are distributed throughout the body. Biological functions of adiponectin are multifold ranging from anti-diabetic, anti-atherogenic, anti-inflammatory to anti-cancer. Lower adiponectin levels have been associated with metabolic syndrome, type 2 diabetes, insulin resistance, cardiovascular diseases, and hypertension. A plethora of experimental evidence supports the role of obesity and increased adiposity in multiple cancers including breast, liver, pancreatic, prostrate, ovarian, and colorectal cancers. Obesity mediates its effect on cancer progression via dysregulation of adipocytokines including increased production of oncogenic adipokine leptin along with decreased production of adiponectin. Multiple studies have shown the protective role of adiponectin in obesity-associated diseases and cancer. Adiponectin modulates multiple signaling pathways to exert its physiological and protective functions. Many studies over the years have shown the beneficial effect of adiponectin in cancer regression and put forth various innovative ways to increase adiponectin levels.

Gold nanorod embedded reduction responsive block copolymer micelle-triggered drug delivery combined with photothermal ablation for targeted cancer therapy.

BACKGROUND: Gold nanorods, by virtue of surface plasmon resonance, convert incident light energy (NIR) into heat energy which induces hyperthermia. We designed unique, multifunctional, gold nanorod embedded block copolymer micelle loaded with GW627368X for targeted drug delivery and photothermal therapy. METHODS: Glutathione responsive diblock co-polymer was synthesized by RAFT process forming self-assembled micelle on gold nanorods prepared by seed mediated method and GW627368X was loaded on to the reduction responsive gold nanorod embedded micelle. Photothermal therapy was administered using cwNIR laser (808nm; 4W/cm2). Efficacy of nanoformulated GW627368X, photothermal therapy and combination of both were evaluated in vitro and in vivo. RESULTS: In response to photothermal treatment, cells undergo regulated, patterned cell death by necroptosis. Combining GW627368X with photothermal treatment using single nanoparticle enhanced therapeutic outcome. In addition, these nanoparticles are effective X-ray CT contrast agents, thus, can help in monitoring treatment. CONCLUSION: Reduction responsive nanorod embedded micelle containing folic acid and lipoic acid when treated on cervical cancer cells or tumour bearing mice, aggregate in and around cancer cells. Due to high glutathione concentration, micelles degrade releasing drug which binds surface receptors inducing apoptosis. When incident with 808nm cwNIR lasers, gold nanorods bring about photothermal effect leading to hyperthermic cell death by necroptosis. Combination of the two modalities enhances therapeutic efficacy by inducing both forms of cell death. GENERAL SIGNIFICANCE: Our proposed treatment strategy achieves photothermal therapy and targeted drug delivery simultaneously. It can prove useful in overcoming general toxicities associated with chemotherapeutics and intrinsic/acquired resistance to chemo and radiotherapy.

Cooperative effect of BI-69A11 and celecoxib enhances radiosensitization by modulating DNA damage repair in colon carcinoma.

Amplification of PI3K-Akt pathway promotes radioresistance in various cancers including colorectal carcinoma. Local recurrence in colon cancer causes poor prognosis affecting overall survival of cancer-affected patient population. To avoid local recurrence, pre-operative or post-operative additional radiotherapy is given. However, main concern regarding radiotherapy is to increase the radiosensitivity of malignant cell without hampering the activities of normal cells. In this context, addition of two or more than two chemotherapeutic drugs as a radiosensitizer is a common practice in radiation biology. BI-69A11 earlier showed potential apoptosis-inducing effect in melanoma and colon carcinoma. Celecoxib showed anti-cancer effects in both COX-2 dependent and independent pathways and used to act as a radiosensitizing enhancer. Here, we suggest that the combination of BI-69A11 and celecoxib inhibits the phosphorylation of ataxia telangiectasia mutated (ATM) kinase and DNA-PK responsible for ionizing radiation (IR)-induced double-strand break (DSB) repair. Moreover, the combinatorial effect of BI-69A11 and celecoxib attenuates the IR-induced G2/M cell cycle arrest. Furthermore, this combination also impairs IR-induced activation of Akt and downstream targets of ATM. This might lead to induced activation of apoptotic pathway after triple therapy treatment modulating pro-apoptotic and anti-apoptotic proteins. This activation of apoptotic pathway also showed the interdependence of PUMA and BAD in triple combination-treated colon cancer cells in a p53 independent manner. This study reveals the therapeutic potential of the triple combination therapy in prevention of radioresistance. Besides, it also demonstrates the cytotoxic effects of triple combination therapy in colon cancer. This study shows utility and potential implication on safety of the patients undergoing radiation therapy.

Thymoquinone restores radiation-induced TGF-ß expression and abrogates EMT in chemoradiotherapy of breast cancer cells.

Radiotherapy remains a prime approach to adjuvant therapies in patients with early and advanced breast cancer. In spite of therapeutic success, metastatic progression in patients undergoing therapy, limits its application. However, effective therapeutic strategies to understand the cellular and molecular machinery in inhibiting radiation-induced metastatic progression, which is poorly understood so far, need to be strengthened. Ionizing radiation was known to prompt cancer cell's metastatic ability by eliciting Transforming Growth Factor-beta (TGF-ß), a key regulator in epithelial-mesenchymal transdifferentiation and radio-resistance. In this viewpoint, we employed thymoquinone as a radiosensitizer to investigate its migration and invasion reversal abilities in irradiated breast cancer cell lines by assessing their respective attributes. The role of metastasis regulatory molecules like TGF-ß, E-cadherin, and integrin αV and its downstream molecules were determined using RT-PCR, western blotting, immunofluorescence, and extracellular TGF-ß levels affirmed through ELISA assays. These studies affirmed the TGF-ß restoring ability of thymoquinone in radiation-driven migration and invasion. Also, results demonstrated that the epithelial markers E-cadherin and cytokeratin 19 were downregulated whereas mesenchymal markers like integrin αV, MMP9, and MMP2 were upregulated by irradiation treatment; however thymoquinone pre-sensitization has reverted the expression of these proteins back to control proteins expression. Here, paclitaxel was chosen as an apoptosis inducer in TGF-ß restored cells and confirmed its cytotoxic effects in radiation alone and thymoquinone sensitized irradiated cells. We conclude that this therapeutic modality is effective in preventing radiation-induced epithelial-mesenchymal transdifferentiation and concomitant induction of apoptosis in breast cancer.

Identification of RAB2A and PRDX1 as the potential biomarkers for oral squamous cell carcinoma using mass spectrometry-based comparative proteomic approach.

Despite the recent advances in diagnostic and therapeutic strategies, oral squamous cell carcinoma (OSCC) remains a major health burden. Protein biomarker discovery for early detection will help to improve patient survival rate in OSCC. Mass spectrometry-based proteomics has emerged as an excellent approach for detection of protein biomarkers in various types of cancers. In the current study, we have used 4-Plex isobaric tags for relative and absolute quantitation (iTRAQ)-based shotgun quantitative proteomic approach to identify proteins that are differentially expressed in cancerous tissues compared to normal tissues. The high-resolution mass spectrometric analysis resulted in identifying 2,074 proteins, among which 288 proteins were differentially expressed. Further, it was noticed that 162 proteins were upregulated, while 125 proteins were downregulated in OSCC-derived cancer tissue samples as compared to the adjacent normal tissues. We identified some of the known molecules which were reported earlier in OSCC such as MMP-9 (8.4-fold), ZNF142 (5.6-fold), and S100A7 (3.5-fold). Apart from this, we have also identified some novel signature proteins which have not been reported earlier in OSCC including ras-related protein Rab-2A isoform, RAB2A (4.6-fold), and peroxiredoxin-1, PRDX1 (2.2-fold). The immunohistochemistry-based validation using tissue microarray slides in OSCC revealed overexpression of the RAB2A and PRDX1 gene in 80 and 68 % of the tested clinical cases, respectively. This study will not only serve as a resource of candidate biomarkers but will contribute towards the existing knowledge on the role of the candidate molecules towards disease progression and therapeutic potential.

The gut microbiota in breast cancer development and treatment: The good, the bad, and the useful!

Regardless of the global progress in early diagnosis and novel therapeutic regimens, breast carcinoma poses a devastating threat, and the advances are somewhat marred by high mortality rates. Breast cancer risk prediction models based on the known risk factors are extremely useful, but a large number of breast cancers develop in women with no/low known risk. The gut microbiome exerts a profound impact on the host health and physiology and has emerged as a pivotal frontier in breast cancer pathogenesis. Progress in metagenomic analysis has enabled the identification of specific changes in the host microbial signature. In this review, we discuss the microbial and metabolomic changes associated with breast cancer initiation and metastatic progression. We summarize the bidirectional impact of various breast cancer-related therapies on gut microbiota and vice-versa. Finally, we discuss the strategies to modulate the gut microbiota toward a more favorable state that confers anticancer effects.

Concomitant analyses of intratumoral microbiota and genomic features reveal distinct racial differences in breast cancer.

Racial disparities are most accentuated among Black women as their lifetime risk of breast cancer incidence is lower than white and Asian women but their breast cancer related mortality is the highest among all races. Black women are more likely to develop triple-negative breast cancer at a younger age and harbor more aggressive tumors. In addition to tumor-centric alterations, tumor growth is also influenced by multiple other tumor microenvironment-related features, including resident immune cells and microbiota. Hence, in this study, we conduct concurrent genomic and metagenomic analyses, and uncover distinctive intratumoral microbial community compositions and tumor immune microenvironment-related traits in breast tumors from Asian, Black and white women. Interestingly, unique racially associated genomic nodes are found in the breast tumors from Asian, Black and white women. Examination of the cellular heterogeneity show differential enrichment of 11 out of 64 immune and stroma cell types in the breast tumors from different racial groups. In terms of microbial diversity, significant differences are revealed in alpha and beta-diversity measures. Intriguingly, potential race-specific microbial biomarkers of breast cancer are identified which significantly correlate with genes involved with tumor aggressiveness, angiogenesis, tumor cell migration and metastasis as well as oncogenic pathways-GLI and Notch. Investigating the metabolic features of intratumoral microbes, we find a significant differential enrichment of environmental information processing pathways, oncogenic pathways, and lipid metabolism pathways. Concomitantly investigating tumor-centric, tumor immune microenvironment-related and microbial alterations, our study provides a comprehensive understanding of racial disparities in breast cancer and warrants further exploration.

Role of Gut Microbiota in Breast Cancer and Drug Resistance.

Breast cancer is the most common malignancy in women worldwide. The cause of cancer is multifactorial. An early diagnosis and the appropriate treatment of cancer can improve the chances of survival. Recent studies have shown that breast cancer is influenced by the microbiota. Different microbial signatures have been identified in the breast microbiota, which have different patterns depending on the stage and biological subgroups. The human digestive system contains approximately 100 trillion bacteria. The gut microbiota is an emerging field of research that is associated with specific biological processes in many diseases, including cardiovascular disease, obesity, diabetes, brain disease, rheumatoid arthritis, and cancer. In this review article, we discuss the impact of the microbiota on breast cancer, with a primary focus on the gut microbiota's regulation of the breast cancer microenvironment. Ultimately, updates on how immunotherapy can affect the breast cancer-based microbiome and further clinical trials on the breast and microbiome axis may be an important piece of the puzzle in better predicting breast cancer risk and prognosis.

Gut colonization with an obesity-associated enteropathogenic microbe modulates the premetastatic niches to promote breast cancer lung and liver metastasis.

Introduction: Obesity, an independent risk factor for breast cancer growth and metastatic progression, is also closely intertwined with gut dysbiosis; and both obese state and dysbiosis promote each other. Enteric abundance of Bacteroides fragilis is strongly linked with obesity, and we recently discovered the presence of B. fragilis in malignant breast cancer. Given that enterotoxigenic B. fragilis or ETBF, which secretes B. fragilis toxin (BFT), has been identified as a procarcinogenic microbe in breast cancer, it is necessary to examine its impact on distant metastasis and underlying systemic and localized alterations promoting metastatic progression of breast cancer. Methods: We used syngeneic mammary intraductal (MIND) model harboring gut colonization with ETBF to query distant metastasis of breast cancer cells. Alterations in the immune network and cytokines/chemokines in the tumor microenvironment and distant metastatic sites were examined using flow cytometry, immunohistochemistry, and multiplex arrays. Results: ETBF infection initiates a systemic inflammation aiding in the establishment of the premetastatic niche formation in vital organs via increased proinflammatory and protumorigenic cytokines like IL17A, IL17E, IL27p28, IL17A/F, IL6, and IL10 in addition to creating a prometastatic immunosuppressive environment in the liver and lungs rich in myeloid cells, macrophages, and T regulatory cells. It induces remodeling of the tumor microenvironment via immune cell and stroma infiltration, increased vasculogenesis, and an EMT-like response, thereby encouraging early metastatic dissemination ready to colonize the conducive environment in liver and lungs of the breast tumor-bearing mice. Discussion: In this study, we show that enteric ETBF infection concomitantly induces systemic inflammation, reshapes the tumor immune microenvironment, and creates conducive metastatic niches to potentiate early dissemination and seeding of metastases to liver and lung tissues in agreement with the "seed and soil hypothesis." Our results also support the ETBF-induced "parallel model" of metastasis that advocates for an early dissemination of tumor cells that form metastatic lesions independent of the primary tumor load.

Unwanted passengers: Microbes hitchiking in breast cancer metastases.

In a recent Cell paper, Fu et al. bridge descriptive cancer microbiome research with mechanistic and functional insight. With savvy use of antibiotics, the authors demonstrate divergent roles of the gut and intratumoral microbiome in breast tumor growth and metastasis, providing potentially actionable tools for better breast cancer management.

Label-Free Vibrational and Quantitative Phase Microscopy Reveals Remarkable Pathogen-Induced Morphomolecular Divergence in Tumor-Derived Cells.

Delineating the molecular and morphological changes that cancer cells undergo in response to extracellular stimuli is crucial for identifying factors that promote tumor progression. Label-free optical imaging offers a potentially promising route for retrieving such single-cell information by generating detailed visualization of the morphology and determining alterations in biomolecular composition. The potential of such nonperturbative morphomolecular microscopy for analyzing microbiota-cancer cell interactions has been surprisingly underappreciated, despite the growing evidence of the critical role of dysbiosis in malignant transformations. Here, using a model system of breast cancer cells, we show that label-free Raman microspectroscopy and quantitative phase microscopy can detect biomolecular and morphological changes in single cells exposed to Bacteroides fragilis toxin (BFT), a toxin secreted by enterotoxigenicB. fragilis. Remarkably, using machine learning to elucidate subtle, but consistent, cellular differences, we found that the morphomolecular differences between BFT-exposed and control breast cancer cells became more accentuated after in vivo passage, corroborating our findings that a short-term BFT exposure imparts a long-term effect on cancer cells and promotes a more invasive phenotype. Complementing more classical labeling techniques, our label-free platform offers a global detection approach with measurements representative of the overall cellular phenotype, paving the way for further investigations into the multifaceted interactions between the cancer cell and the microbiota.

The Microbiome and Cancer: Creating Friendly Neighborhoods and Removing the Foes Within.

The human body is colonized by the microbial cells that are estimated to be as abundant as human cells, yet their genome is roughly 100 times the human genome, providing significantly more genetic diversity. The past decade has observed an explosion of interest in examining the existence of microbiota in the human body and understanding its role in various diseases including inflammatory bowel disease, neurologic diseases, cardiovascular disorders, and cancer. Many studies have demonstrated differential community composition between normal tissue and cancerous tissue, paving the way for investigations focused on deciphering the cause-and-effect relationships between specific microbes and initiation and progression of various cancers. Also, evolving are the strategies to alter tumor-associated dysbiosis and move it toward eubiosis with holistic approaches to change the entire neighborhood or to neutralize pathogenic strains. In this review, we discuss important pathogenic bacteria and the underlying mechanisms by which they affect cancer progression. We summarize key microbiota alterations observed in multiple tumor niches, their association with clinical stages, and their potential use in cancer diagnosis and management. Finally, we discuss microbiota-based therapeutic approaches.

Role of Omentin in Obesity Paradox in Lung Cancer.

Lung cancer remains the second-most-common cancer worldwide and is associated with the highest number of cancer-related mortality. While tobacco smoking is the most important risk factor for lung cancer, many other lifestyles and occupational factors significantly contribute. Obesity is a growing global health concern and contributes to ~30% cancer-related mortality, but unlike other lifestyle diseases, lung cancer is negatively associated with obesity. We meta-analyzed multiple case-control studies confirming increased survival and better outcomes in overweight and obese lung cancer patients. Tumor heterogeneity analysis showed significant enrichment of adipocytes and preadipocytes in normal lungs compared to lung cancers. Interestingly, one of the understudied adipokine, omentin, was significantly and consistently lower in lung neoplasms compared to normal lungs. Omentin has been examined in relation to osteoarthritis, inflammatory bowel disease, cardiovascular diseases, diabetes, chronic liver disease, psoriasis and some other cancers. Aberrant expression of omentin has been reported in solid tumors; however, little is known about its role in lung cancer. We found omentin to be consistently downregulated in lung cancers, and it exhibited a negative correlation with important transcription factors FOXA1, EN1, FOXC1 and ELK4. We, therefore, suggest that omentin may serve as a prognostic factor in lung cancer and explain the "obesity paradox" in lung cancer.

Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation.

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.

Concomitant activation of GLI1 and Notch1 contributes to racial disparity of human triple negative breast cancer progression.

Mortality from triple negative breast cancer (TNBC) is significantly higher in African American (AA) women compared to White American (WA) women emphasizing ethnicity as a major risk factor; however, the molecular determinants that drive aggressive progression of AA-TNBC remain elusive. Here, we demonstrate for the first time that AA-TNBC cells are inherently aggressive, exhibiting elevated growth, migration, and cancer stem-like phenotype compared to WA-TNBC cells. Meta-analysis of RNA-sequencing data of multiple AA- and WA-TNBC cell lines shows enrichment of GLI1 and Notch1 pathways in AA-TNBC cells. Enrichment of GLI1 and Notch1 pathway genes was observed in AA-TNBC. In line with this observation, analysis of TCGA dataset reveals a positive correlation between GLI1 and Notch1 in AA-TNBC and a negative correlation in WA-TNBC. Increased nuclear localization and interaction between GLI1 and Notch1 is observed in AA-TNBC cells. Of importance, inhibition of GLI1 and Notch1 synergistically improves the efficacy of chemotherapy in AA-TNBC cells. Combined treatment of AA-TNBC-derived tumors with GANT61, DAPT, and doxorubicin/carboplatin results in significant tumor regression, and tumor-dissociated cells show mitigated migration, invasion, mammosphere formation, and CD44+/CD24- population. Indeed, secondary tumors derived from triple-therapy-treated AA-TNBC tumors show diminished stem-like phenotype. Finally, we show that TNBC tumors from AA women express significantly higher level of GLI1 and Notch1 expression in comparison to TNBC tumors from WA women. This work sheds light on the racial disparity in TNBC, implicates the GLI1 and Notch1 axis as its functional mediators, and proposes a triple-combination therapy that can prove beneficial for AA-TNBC.

Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen by coordinating a crosstalk between Med1, miR205 and ErbB.

Obese women with hormone receptor-positive breast cancer exhibit poor response to therapy and inferior outcomes. However, the underlying molecular mechanisms by which obesity/hyperleptinemia may reduce the efficacy of hormonal therapy remain elusive. Obese mice with hyperleptinemia exhibit increased tumor progression and respond poorly to tamoxifen compared to non-obese mice. Exogenous leptin abrogates tamoxifen-mediated growth inhibition and potentiates breast tumor growth even in the presence of tamoxifen. Mechanistically, leptin induces nuclear translocation of phosphorylated-ER and increases the expression of ER-responsive genes, while reducing tamoxifen-mediated gene repression by abrogating tamoxifen-induced recruitment of corepressors NCoR, SMRT, and Mi2 and potentiating coactivator binding. Furthermore, in silico analysis revealed that coactivator Med1 potentially associates with 48 (out of 74) obesity-signature genes. Interestingly, leptin upregulates Med1 expression by decreasing miR-205, and increases its functional activation via phosphorylation, which is mediated by activation of Her2 and EGFR. It is important to note that Med1 silencing abrogates the negative effects of leptin on tamoxifen efficacy. In addition, honokiol or adiponectin treatment effectively inhibits leptin-induced Med1 expression and improves tamoxifen efficacy in hyperleptinemic state. These studies uncover the mechanistic insights how obese/hyperleptinemic state may contribute to poor response to tamoxifen implicating leptin-miR205-Med1 and leptin-Her2-EGFR-Med1 axes, and present bioactive compound honokiol and adipocytokine adiponectin as agents that can block leptin's negative effect on tamoxifen.

A Procarcinogenic Colon Microbe Promotes Breast Tumorigenesis and Metastatic Progression and Concomitantly Activates Notch and ß-Catenin Axes.

The existence of distinct breast microbiota has been recently established, but their biological impact in breast cancer remains elusive. Focusing on the shift in microbial community composition in diseased breast compared with normal breast, we identified the presence of Bacteroides fragilis in cancerous breast. Mammary gland as well as gut colonization with enterotoxigenic Bacteroides fragilis (ETBF), which secretes B. fragilis toxin (BFT), rapidly induces epithelial hyperplasia in the mammary gland. Breast cancer cells exposed to BFT exhibit "BFT memory" from the initial exposure. Intriguingly, gut or breast duct colonization with ETBF strongly induces growth and metastatic progression of tumor cells implanted in mammary ducts, in contrast to nontoxigenic Bacteroides fragilis. This work sheds light on the oncogenic impact of a procarcinogenic colon bacterium ETBF on breast cancer progression, implicates the ß-catenin and Notch1 axis as its functional mediators, and proposes the concept of "BFT memory" that can have far-reaching biological implications after initial exposure to ETBF. SIGNIFICANCE: B. fragilis is an inhabitant of breast tissue, and gut or mammary duct colonization with ETBF triggers epithelial hyperplasia and augments breast cancer growth and metastasis. Short-term exposure to BFT elicits a "BFT memory" with long-term implications, functionally mediated by the ß-catenin and Notch1 pathways.This article is highlighted in the In This Issue feature, p. 995.

Microbial Alterations and Risk Factors of Breast Cancer: Connections and Mechanistic Insights.

Breast cancer-related mortality remains high worldwide, despite tremendous advances in diagnostics and therapeutics; hence, the quest for better strategies for disease management, as well as the identification of modifiable risk factors, continues. With recent leaps in genomic technologies, microbiota have emerged as major players in most cancers, including breast cancer. Interestingly, microbial alterations have been observed with some of the established risk factors of breast cancer, such as obesity, aging and periodontal disease. Higher levels of estrogen, a risk factor for breast cancer that cross-talks with other risk factors such as alcohol intake, obesity, parity, breastfeeding, early menarche and late menopause, are also modulated by microbial dysbiosis. In this review, we discuss the association between known breast cancer risk factors and altered microbiota. An important question related to microbial dysbiosis and cancer is the underlying mechanisms by which alterations in microbiota can support cancer progression. To this end, we review the involvement of microbial metabolites as effector molecules, the modulation of the metabolism of xenobiotics, the induction of systemic immune modulation, and altered responses to therapy owing to microbial dysbiosis. Given the association of breast cancer risk factors with microbial dysbiosis and the multitude of mechanisms altered by dysbiotic microbiota, an impaired microbiome is, in itself, an important risk factor.

Synthesis and characterization of PCL-DA:PEG-DA based polymeric blends grafted with SMA hydrogel as bio-degradable intrauterine contraceptive implant.

Presently available long-acting reversible female contraceptive implants are said to be an effective way of preventing unintended pregnancy. Unacceptable side effects attributed by these contraceptive implants act as a major drawback for the practitioners. These problems pave the way for the development of a new form of long-acting non-hormonal female contraceptive implant, especially in the developing countries. PCL-DA: PEG-DA polymeric scaffold is grafted with Styrene Maleic Anhydride (SMA) based hydrogel, and their physicochemical, thermal and biological parameters are being explored for developing a bio-degradable form of the non-hormonal intrauterine contraceptive implant. With the fixed ratio of PEG-DA: PCL-DA polymer, SMA hydrogel was added at four different concentrations to determine the optimum concentration of SMA hydrogel for the development of a promising long-acting biodegradable intrauterine contraceptive implant. Structural elucidation of the polymers was confirmed using 1H and 13C NMR spectroscopic analyses. The physiochemical characterization report suggests that SMA hydrogel interacts with the PCL-DA: PEG-DA polymeric scaffold through intermolecular hydrogen bonding interaction. The in-vitro spermicidal activity of the polymeric scaffold increases when the concentration of SMA based hydrogel in the polymer samples is increased without showing any significant toxicological effects. From the study results, it may be concluded that SMA hydrogel grafted PCL-DA: PEG-DA scaffold can be developed as intra-uterine biodegradable non-hormonal female contraceptive implant due to its excellent bio-compatibility and spermicidal activity.