Predictors of Sustained Response With Tofacitinib Therapy in Patients With Ulcerative Colitis.

BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We evaluate baseline characteristics as predictors of sustained response and remission in patients with ulcerative colitis receiving tofacitinib maintenance therapy. METHODS: Patients with clinical response following OCTAVE Induction 1 and 2 entered OCTAVE Sustain and were rerandomized to receive tofacitinib 5 or 10 mg twice daily or placebo. Baseline characteristics were stratified by week 52 efficacy endpoints (remission, sustained remission, clinical response, sustained clinical response). Associations between baseline characteristics and efficacy endpoints were evaluated using logistic regression analyses. RESULTS: Overall, 170 of 487 (34.9%) patients were in remission at week 52. In multivariable modeling, endoscopic subscore at baseline of OCTAVE Induction 1 and 2 (2 vs 3; odds ratio [OR], 1.60; 95% confidence interval [CI], 1.06-2.44]), partial Mayo score (<2 vs ≥2; OR, 1.92; 95% CI, 1.27-2.90), and age (per 10-years; OR, 1.19; 95% CI, 1.02-1.39) at baseline of OCTAVE Sustain (following 8 weeks' tofacitinib induction therapy) were associated with higher odds of remission at week 52. Oral corticosteroid use (OR, 0.63; 95% CI, 0.42-0.96) and C-reactive protein (per unit; OR, 0.94; 95% CI, 0.89-0.99) at baseline of OCTAVE Sustain were associated with reduced likelihood of remission at week 52. In general, opposite associations were observed for time to loss of response. CONCLUSION: Patients with greater clinical improvement after 8 weeks of tofacitinib induction therapy are more likely to maintain response or remission with tofacitinib regardless of dose received during maintenance, highlighting the importance of a robust response to induction therapy.

The Role of lncRNAs in Rare Tumors with a Focus on HOX Transcript Antisense RNA (HOTAIR).

Rare cancers are identified as those with an annual incidence of fewer than 6 per 100,000 persons and includes both epithelial and stromal tumors from different anatomical areas. The advancement of analytical methods has produced an accurate molecular characterization of most human cancers, suggesting a "molecular classification" that has allowed the establishment of increasingly personalized therapeutic strategies. However, the limited availability of rare cancer samples has resulted in very few therapeutic options for these tumors, often leading to poor prognosis. Long non coding RNAs (lncRNAs) are a class of non-coding RNAs mostly involved in tumor progression and drug response. In particular, the lncRNA HOX transcript antisense RNA (HOTAIR) represents an emergent diagnostic, prognostic and predictive biomarker in many human cancers. The aim of this review is to highlight the role of HOTAIR in rare cancers, proposing it as a new biomarker usable in the management of these tumors.

Aberrant Expression of Long Non Coding RNA HOTAIR and De-Regulation of the Paralogous 13 HOX Genes Are Strongly Associated with Aggressive Behavior of Gastro-Entero-Pancreatic Neuroendocrine Tumors.

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets.

Vaccinations in patients with inflammatory bowel disease.

Treatment of inflammatory bowel disease (IBD) frequently requires administration of immunosuppressive therapies, which increases susceptibility to a number of infectious pathogens. However, many infections can be prevented by correct and appropriate utilization of vaccinations. While several guidelines have been published on vaccination schedules in patients with IBD, vaccination rates remain suboptimal and even lower than those in the general population. This is due to many factors including poor awareness of the importance of vaccines by gastroenterologists and general practitioners as well as potential prejudices of patients regarding the safety and benefits of vaccines. With the aim of increasing awareness about the key role of immunization in the management of patients with IBD, the present review examines the existing literature relating to the main vaccinations and their application in these patients. We also summarize current evidence in order to provide clinicians with an easy source of reference for the principal recommendations for prevention of infectious diseases in patients with IBD. In addition, the recommendations about traveling for IBD patients are briefly explored. Lastly, since it is important for gastroenterologists to be aware of recommendations on vaccination, we recommend implementing educational programs to ensure compliance with current guidelines.

Quality of life in patients with moderate to severe ulcerative colitis and the impact of treatment: A narrative review.

As a chronic inflammatory disease, ulcerative colitis has significant negative impact on the quality of life (QoL) of patients. Since the disease affects many aspects of QoL, comprising multiple domains, treatments that induce and maintain remission can provide benefits beyond hard clinical endpoints. Effective treatment of ulcerative colitis can restore QoL and return it to normal or near normal levels. Biological therapies have shown consistent improvement in the QoL of patients with ulcerative colitis during the induction phase, with benefits that are generally maintained in the long-term. Current medical treatment options broadly comprise aminosalicylates, corticosteroids, thiopurines, and calcineurin inhibitors, as well as biologic therapies. Conventional therapies do not always adequately control disease in a sizeable portion of patients, while anti-TNF antibodies are associated with several issues such as contraindications, intolerance, primary non-response, and loss of response in some patients. JAK inhibitors have been associated with clinical improvements in disease manifestations and long-term improvement in QoL outcomes. However, additional studies are needed to better understand the comparative effects of different treatments on QoL and patient preferences for therapy. Herein, the available evidence is reviewed regarding the impact of various treatments on QoL in patients with moderate to severe ulcerative colitis.

Author Correction: Pro-inflammatory cytokines activate hypoxia-inducible factor 3α via epigenetic changes in mesenchymal stromal/stem cells.

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

Genetic trajectory and immune microenvironment of lung-specific oligometastatic colorectal cancer.

Genetics and immunologic dynamics pushing the evolution of colorectal cancer (CRC) from the primary tumor to the metastases are largely unknown; cancer heterogeneity makes challenging both therapy and mechanistic studies. We selected patients developing CRC with lung-limited metastatic disease as only illness during their life in order to find any relevant genotype-phenotype relationship. Analysis of 523 cancer-relevant genes and of immune cells infiltration in primary and metastatic tissues revealed atypical genomic trajectories (TMB decrease, KRAS and SMAD4 regressive mutations), specific genetic events (ERBB2 point mutations) and scarce T-cell infiltration. These insights provide novel information in oligometastatic CRC biology and new perspectives for cancer monitoring and anti-cancer therapeutic strategies.

Unmet Medical Needs in the Management of Ulcerative Colitis: Results of an Italian Delphi Consensus.

BACKGROUND: The lifelong and remitting nature of ulcerative colitis results in considerable disability and a substantial negative impact on quality of life. The major goal of the therapy of ulcerative colitis is considered to be the modification of the course of the disease, so that the patient's quality of life can be improved while minimising disease-related disability. Although considerable progress in understanding the molecular pathways involved in ulcerative colitis has led to improved treatment options, there is currently no definitive cure for ulcerative colitis, there remain considerable unmet needs in terms of long-term efficacy and safety, and there are many patients who continue to be burdened by physical and psychological symptoms. Defining unmet needs can help to increase the awareness of the shortcomings of current therapeutic management and highlight the need to achieve not only a control of clinical symptoms but also control of mucosal healing, in order to attain the best possible long-term outcomes. METHODS: With the aim of providing a better understanding of the unmet needs of patients towards improving overall care, a Delphi process was used to obtain consensus among a group of Italian ulcerative colitis experts. The consensus group met with a major focus of delineating the unmet needs of current treatment strategies and overall management of ulcerative colitis, while also focusing on quality of life and patient care. RESULTS: Three main areas were identified: (i) treatment, (ii) monitoring and risk management, and (iii) patient-related issues. A high level of consensus was reached on all but one of the statements identified. CONCLUSIONS: The findings arising from the Delphi process provide valuable insights into the unmet needs in the management of moderate-to-severe ulcerative colitis from the clinician's perspective, while emphasising the benefits of therapeutic individualization and suggesting areas that need additional study with the aim of optimising the treatment of patients with ulcerative colitis.

AXL Is a Novel Predictive Factor and Therapeutic Target for Radioactive Iodine Refractory Thyroid Cancer.

Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs.

LncRNA HOTAIR in Tumor Microenvironment: What Role?

lncRNAs participate in many cellular processes, including regulation of gene expression at the transcriptional and post-transcriptional levels. In addition, many lncRNAs can contribute to the development of different human diseases including cancer. The tumor microenvironment (TME) plays an important role during tumor growth and metastatic progression, and most of these lncRNAs have a key function in TME intracellular signaling. Among the numerous identified lncRNAs, several experimental evidences have shown the fundamental role of the lncRNA HOTAIR in carcinogenesis, also highlighting its use as a circulating biomarker. In this review we described the contribution of HOTAIR in the TME modulation, highlighting its relation with cellular and non-cellular components during tumor evolution and progression.

Pro-inflammatory cytokines activate hypoxia-inducible factor 3α via epigenetic changes in mesenchymal stromal/stem cells.

Human mesenchymal stromal/stem cells (hMSCs) emerged as a promising therapeutic tool for ischemic disorders, due to their ability to regenerate damaged tissues, promote angiogenesis and reduce inflammation, leading to encouraging, but still limited results. The outcomes in clinical trials exploring hMSC therapy are influenced by low cell retention and survival in affected tissues, partially influenced by lesion's microenvironment, where low oxygen conditions (i.e. hypoxia) and inflammation coexist. Hypoxia and inflammation are pathophysiological stresses, sharing common activators, such as hypoxia-inducible factors (HIFs) and NF-κB. HIF1α and HIF2α respond essentially to hypoxia, activating pathways involved in tissue repair. Little is known about the regulation of HIF3α. Here we investigated the role of HIF3α in vitro and in vivo. Human MSCs expressed HIF3α, differentially regulated by pro-inflammatory cytokines in an oxygen-independent manner, a novel and still uncharacterized mechanism, where NF-κB is critical for its expression. We investigated if epigenetic modifications are involved in HIF3α expression by methylation-specific PCR and histone modifications. Robust hypermethylation of histone H3 was observed across HIF3A locus driven by pro-inflammatory cytokines. Experiments in a murine model of arteriotomy highlighted the activation of Hif3α expression in infiltrated inflammatory cells, suggesting a new role for Hif3α in inflammation in vivo.

LncRNA HOTAIR Polymorphisms Association with Cancer Susceptibility in Different Tumor Types.

Single nucleotide polymorphisms (SNPs) in non-coding RNAs (ncRNA) molecules affect gene and protein expression and generate genetic variability influencing the risk of tumor diseases. HOTAIR locates at the heart of the cell memory gene program and represents a prototype of long non coding RNA (LncRNA) due to its capacity to regulate in-trans a distant chromosome landscape. Aberrant expression of HOTAIR is frequently associated with pathogenesis and mostly with metastatic progression of several human cancers. Different polymorphisms, particularly present in intronic sequences, as well as in promoter regions of HOTAIR, are often associated with its aberrant expression, patient prognosis, and cancer susceptibility in different tumor phenotypes. In this minireview, we have summarized the main SNPs in HOTAIR sequence and their relation with cancer risk in several types of solid tumors.

Mucosa-associated microbiota dysbiosis in colitis associated cancer.

Gut microbiota dysbiosis has been associated with inflammatory bowel diseases (IBD). In colorectal cancer, the gut microbiota has also been recognized as potentially involved in aggravating or favoring the tumor development. However, very little is known on the structure and role of the microbiota in colitis associated cancer (CAC), an important complication of IBD in human. Here we analyzed the bacterial and fungal composition of the mucosa associated microbiota of patients suffering CAC, sporadic cancer (SC) and of healthy subjects (HS) by barcode sequences analysis on the following cohort: 7 CAC patients, 10 SC patients and 10 HS using 16S (MiSeq) and ITS2 (pyrosequencing) sequencing, for bacteria and fungi respectively. Mucosa-associated bacterial microbiota in CAC was significantly different from the ones in SC or in HS, while the fungal showed no differences. Comparison between mucosa-associated microbiota on the tumor site or in normal mucosa near the tumor showed very similar patterns. The global mucosa-associated bacterial microbiota in cancer patients was characterized by a restriction in biodiversity but no change for the fungal community. Compared to SC, CAC was characterized by an increase of Enterobacteriacae family and Sphingomonas genus and a decrease of Fusobacterium and Ruminococcus genus. Our study confirms the alteration of the mucosa-associated bacterial microbiota in IBD and SC. Although the cohort is limited in number, this is the first evidence of the existence of an altered bacterial microbiota in CAC clearly different from the one in SC patients.

EGFR in Tumor-Associated Myeloid Cells Promotes Development of Colorectal Cancer in Mice and Associates With Outcomes of Patients.

BACKGROUND & AIMS: Inhibitors of the epidermal growth factor receptor (EGFR) are the first-line therapy for patients with metastatic colorectal tumors without RAS mutations. However, EGFR inhibitors are ineffective in these patients, and tumor level of EGFR does not associate with response to therapy. We screened human colorectal tumors for EGFR-positive myeloid cells and investigated their association with patient outcome. We also performed studies in mice to evaluate how EGFR expression in tumor cells and myeloid cells contributes to development of colitis-associated cancer and ApcMin-dependent intestinal tumorigenesis. METHODS: We performed immunohistochemical and immunofluorescent analyses of 116 colorectal tumor biopsies to determine levels of EGFR in tumor and stroma; we also collected information on tumor stage and patient features and outcomes. We used the Mann-Whitney U and Kruskal-Wallis tests to correlate tumor levels of EGFR with tumor stage, and the Kaplan-Meier method to estimate patients' median survival time. We performed experiments in mice lacking EGFR in intestinal epithelial cells (Villin-Cre; Egfrf/f and Villin-CreERT2; Egfrf/f mice) or myeloid cells (LysM-Cre; Egfrf/f mice) on a mixed background. These mice were bred with ApcMin/+ mice; colitis-associated cancer and colitis were induced by administration of dextran sodium sulfate (DSS), with or without azoxymethane (AOM), respectively. Villin-CreERT2 was activated in developed tumors by administration of tamoxifen to mice. Littermates that expressed full-length EGFR were used as controls. Intestinal tissues were collected; severity of colitis, numbers and size of tumors, and intestinal barrier integrity were assessed by histologic, immunohistochemical, quantitative reverse transcription polymerase chain reaction, and flow cytometry analyses. RESULTS: We detected EGFR in myeloid cells in the stroma of human colorectal tumors; myeloid cell expression of EGFR associated with tumor metastasis and shorter patient survival time. Mice with deletion of EGFR from myeloid cells formed significantly fewer and smaller tumors than the respective EGFR-expressing controls in an ApcMin/+ background as well as after administration of AOM and DSS. Deletion of EGFR from intestinal epithelial cells did not affect tumor growth. Furthermore, tamoxifen-induced deletion of EGFR from epithelial cells of established intestinal tumors in mice given AOM and DSS did not reduce tumor size. EGFR signaling in myeloid cells promoted activation of STAT3 and expression of survivin in intestinal tumor cells. Mice with deletion of EGFR from myeloid cells developed more severe colitis after DSS administration, characterized by increased intestinal inflammation and intestinal barrier disruption, than control mice or mice with deletion of EGFR from intestinal epithelial cells. EGFR-deficient myeloid cells in the colon of DSS-treated LysM-Cre; Egfrf/f mice had reduced expression of interleukin 6 (IL6), and epithelial STAT3 activation was reduced compared with controls. Administration of recombinant IL6 to LysM-Cre; Egfrf/f mice given DSS protected them from weight loss and restored epithelial proliferation and STAT3 activation, compared with administration of DSS alone to these mice. CONCLUSIONS: Increased expression of EGFR in myeloid cells from the colorectal tumor stroma associates with tumor progression and reduced survival time of patients with metastatic colorectal cancer. Deletion of EGFR from myeloid cells, but not intestinal epithelial cells, protects mice from colitis-induced intestinal cancer and ApcMin-dependent intestinal tumorigenesis. Myeloid cell expression of EGFR increases activation of STAT3 and expression of survivin in intestinal epithelial cells and expression of IL6 in colon tissues. These findings indicate that expression of EGFR by myeloid cells of the colorectal tumor stroma, rather than the cancer cells themselves, contributes to tumor development.

Diagnosis of anaplastic lymphoma kinase rearrangement in cytological samples through a fluorescence in situ hybridization-based assay: Cytological smears versus cell blocks.

Anaplastic lymphoma kinase (ALK) status analysis of lung cytological specimens should be successfully encouraged in routine practice because biopsy specimens are not always available. To date, the US Food and Drug Administration has approved both fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) as diagnostic tests for identifying ALK-positive patients eligible for treatment with crizotinib. Although ALK IHC is an optimal diagnostic tool, FISH becomes mandatory in equivocal cases. ALK FISH of paraffin-embedded tissue material is still the gold standard, whereas the cytological specimen assay has not yet been completely standardized. Many controversial data have been reported on the adequacy of cytology cell blocks (CBs) versus conventional smears for FISH testing. This review discusses some critical issues related to ALK FISH of cytological samples, including the triaging of collected specimens to optimize the material, the use of CBs versus conventional smears, and alternative methods for an ALK rearrangement diagnosis. Conventional smears have the advantages of an immediate evaluation, no probe tissue-related artifactual loss, no fixation-related alterations, and usually sufficient material for an analytic preparation. On the other hand, CBs have several advantages, including the appropriate conservation of the tissue architecture, an absence of problems related to cell overlapping, and the ability to evaluate neoplastic cells in a dark field. Cancer Cytopathol 2017;125:303-312. © 2017 American Cancer Society.

COX-2 expression positively correlates with PD-L1 expression in human melanoma cells.

BACKGROUND: The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma. METHODS: Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAFV600E A375 and NRASQ61R SK-MEL-2 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on expression of PD-L1 in vitro. RESULTS: BRAFV600E/V600K and NRASQ61R/Q61L were detected in 57.8 and 8.9% of the metastatic lesions, and in 65.9 and 6.8% of the primary tumors, respectively. PD-L1 and COX-2 expression were heterogeneously expressed in both primary melanoma lesions and not matched lymph node metastases. A significantly lower number of PD-L1 negative lesions was found in primary tumors as compared to not matched metastatic lesions (P = 0.002). COX-2 expression significantly correlated with PD-L1 expression in both primary (P = 0.001) and not matched metastatic (P = 0.048) lesions. Furthermore, in melanoma tumors, cancer cells expressing a higher levels of COX-2 also co-expressed a higher level of PD-L1. Lastly, inhibition of COX-2 activity by celecoxib down-regulated the expression of PD-L1 in both BRAFV600E A375 and NRASQ61R SK-MEL-2 melanoma cell lines. CONCLUSIONS: COX-2 expression correlates with and modulates PD-L1 expression in melanoma cells. These findings have clinical relevance since they provide a rationale to implement novel clinical trials to test COX-2 inhibition as a potential treatment to prevent melanoma progression and immune evasion as well as to enhance the anti-tumor activity of PD-1/PD-L1 based immunotherapy for the treatment of melanoma patients with or without BRAF/NRAS mutations.

HOTAIR role in melanoma progression and its identification in the blood of patients with advanced disease.

The molecular mechanisms responsible for the metastatic progression of melanoma have not been fully defined yet. We have recently shown that an important role in this process is certainly played by HOX genes, whose regulation is under control of particular non-coding RNAs, some of which are present within the HOX locus. HOTAIR is the most studied among them, whose aberrant expression is associated with the metastatic progression of many malignancies. The aim of this study was to verify the role played by HOTAIR in metastatic progression of melanoma and to evaluate the circulating levels of HOTAIR in the blood of patients with metastatic melanoma. A series of melanocytic lesions were selected to evaluate the potential changes in the expression of HOTAIR during the evolution of the disease through in situ and molecular approaches. None of the benign melanocytic lesions showed the presence of HOTAIR. The staining of HOTAIR resulted very weak in the primary pT1 lesions, while it was very strong in all pairs of primary tissues and corresponding metastases. Surprisingly, we found the presence of HOTAIR in some intratumoral lymphocytes, while this positivity decreased in lymphocyte component further away from the tumor. HOTAIR was also detected in the serum of selected metastatic patients. These data allowed us to speculate on the fundamental role played by HOTAIR in tumor evolution of melanoma. Its presence in intratumoral lymphocytes might suggest that its involvement in the modulation of tumor microenvironment and the detection in the serum could be used in the management of melanoma patients.

Fungal microbiota dysbiosis in IBD.

OBJECTIVE: The bacterial intestinal microbiota plays major roles in human physiology and IBDs. Although some data suggest a role of the fungal microbiota in IBD pathogenesis, the available data are scarce. The aim of our study was to characterise the faecal fungal microbiota in patients with IBD. DESIGN: Bacterial and fungal composition of the faecal microbiota of 235 patients with IBD and 38 healthy subjects (HS) was determined using 16S and ITS2 sequencing, respectively. The obtained sequences were analysed using the Qiime pipeline to assess composition and diversity. Bacterial and fungal taxa associated with clinical parameters were identified using multivariate association with linear models. Correlation between bacterial and fungal microbiota was investigated using Spearman's test and distance correlation. RESULTS: We observed that fungal microbiota is skewed in IBD, with an increased Basidiomycota/Ascomycota ratio, a decreased proportion of Saccharomyces cerevisiae and an increased proportion of Candida albicans compared with HS. We also identified disease-specific alterations in diversity, indicating that a Crohn's disease-specific gut environment may favour fungi at the expense of bacteria. The concomitant analysis of bacterial and fungal microbiota showed a dense and homogenous correlation network in HS but a dramatically unbalanced network in IBD, suggesting the existence of disease-specific inter-kingdom alterations. CONCLUSIONS: Besides bacterial dysbiosis, our study identifies a distinct fungal microbiota dysbiosis in IBD characterised by alterations in biodiversity and composition. Moreover, we unravel here disease-specific inter-kingdom network alterations in IBD, suggesting that, beyond bacteria, fungi might also play a role in IBD pathogenesis.

Downregulation of androgen receptor is strongly associated with diabetes in triple negative breast cancer patients.

Developing of personalized therapies for Triple Negative Breast Cancer (TNBC) requires a more detailed knowledge of its biology and a correct stratification of molecular subtypes. Androgen Receptor (AR) is expressed in a large part of TNBCs but its prognostic role in this Breast Cancer (BC) subtype is highly debated. In this study, we analyzed AR expression in a series of 238 TNBCs and correlated its expression with clinical-pathological features, survival, and metabolic profile. We showed a consistent association between AR expression and a better prognosis of TNBC patients, while its downregulation appeared strongly associated with diabetic disease. Since a recent prospective study reported a lower BC risk in diabetic women treated with drugs able to reduce circulating levels of glucose compared with non-diabetic woman, and in vitro studies showed that AR level are regulated directly by hyperglycemia, we speculate on the perspective of new integrated therapies for TNBC.