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Supplementary Figure from Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies.Significance:Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor–dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.–related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy.This article is highlighted in the In This Issue feature, p. 873

Despite the low frequency of skin ILCs and the limited number of samples analyzed in this study, our data indicate that ICOS+ ILCs express IL-13Rα1 and that the density of ICOS+ ILCs decreased four weeks after initiation of treatment with tralokinumab.

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies. Significance: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor–dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.–related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873

BACKGROUND/AIM The present study examined the impact of systemic inflammatory markers including C-reactive protein (CRP)/Albumin (Alb) and neutrophil lymphocyte ratio (NLR)/Alb on the prognosis of patients treated with first line molecular targeted therapy for advanced RCC. PATIENTS AND METHODS A total of 131 patients with advanced RCC treated with molecular targeted therapy as first line treatment from May 2008 to April 2019 were retrospectively analyzed. RESULTS High CRP, high NLR, low Alb and high CRP/Alb showed significantly worse progression-free survival (PFS) and overall survival (OS) than low CRP, low NLR, high Alb, low CRP/Alb and low NLR/Alb, respectively. In multivariate analyses, prior nephrectomy (p=0.0321) and NLR/Alb ratio (p=0.0327) were independent prognostic factors for PFS. Furthermore, prior nephrectomy (p=0.0013) and CRP/Alb ratio (p=0.0020) were independent prognostic factors for OS. CONCLUSION CRP/Alb and NLR/Alb ratios are useful and independent prognostic biomarkers in patients with advanced RCC treated with molecular targeted therapy.

This case report describes a 17-year-old male patient with frog spawn–like vesicles around the urethra.

International audience; Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

Simple Summary Ecotropic viral integration site 2B (EVI2B) is a protein-coding gene known as a lymphocyte-specific marker in peripheral blood. However, the prognostic value of EVI2B expression in metastatic melanoma tissue and its detailed profile of tumor-infiltrating lymphocytes are still unclear. In publicly available datasets, we found that increased EVI2B was significantly associated with longer prognoses such as overall survival and disease-specific survival. The EVI2B-high melanoma tissue had a favorable distribution/clustering pattern of infiltrating lymphocytes with increased CD8+ T cells over regulatory T cells. Moreover, EVI2B expression correlated with multiple immunomodulatory genes including IFN-γ signature genes. In conclusion, EVI2B is a prognostic biomarker with IFN-γ associated immune infiltration in metastatic melanoma. Abstract Background: To assess the prognostic role and the antitumor immunological relevance of ecotropic viral integration site 2B (EVI2B) in metastatic melanoma. Methods: In this study, we integrated clinical data, mRNA expression data, and the distribution and fraction of tumor infiltrating lymphocytes (TILs) using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE65904 and GSE19234). Results: The univariate and multivariate analyses showed that higher gene expression of EVI2B was significantly associated with longer prognoses. The EVI2B-high melanoma tissue had favorable histological parameters such as a brisk global distribution pattern and clustering structure of TILs (i.e., Banfield and Raftery index) with enriched CD8+ T cells over regulatory T cells and increased cytotoxicity scores. In addition, EVI2B expression positively correlated with IFN-γ signature genes (CXCL10, CXCL9, HLA-DRA, IDO1, IFNG, and STAT1) and other various immunomodulatory genes. Conclusion: EVI2B is a novel prognostic biomarker with IFN-γ associated immune infiltration in metastatic melanoma.

Background/aim The present study aimed to examine the influence of antibiotics (AB) on the clinical outcomes of Japanese patients treated with immune check point inhibitors (ICIs) for metastatic renal cell carcinoma (RCC) patients. Patients and methods A total of 31 patients with metastatic RCC treated with ICIs from November 2016 to April 2019 were retrospectively reviewed and analyzed. Results Five patients were treated with AB prior to ICIs treatment. Median progression free survival (PFS) of patients treated with AB vs. patients not treated with AB was 2.8 months and 18.4 months, respectively. The difference between PFS was statistically significant (p=0.0004). In multivariate analyses, AB use (p=0.0377) and presence of immune related adverse events (p=0.0042) were independent prognostic factors for PFS in association with ICIs therapy. Conclusion The use of AB before ICIs treatment was a predictor of poor ICIs response in metastatic RCC.

FXYD3 is a protein-coding gene, belonging to the FXYD protein family associated with Na+/K+-ATPase enzymes and chloride ion channels. Accumulating evidence suggests the biological role of FXYD3 in multiple cancers. However, the prognostic value of FXYD3 expression in clear renal cell carcinoma (KIRC) is unclear. Therefore, we evaluated the clinical data with tumor-infiltrating lymphocytes (TILs) and immunoinhibitory gene expression data using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset (GSE29609). First, the FXYD3 high KIRC patients had distinct clinical characteristics, including age, sex, disease stage, histological grade, and hypoxia-related gene expressions. Next, FXYD3 gene expression was correlated with poor overall survival in both TCGA and GSE29609 cohorts. The ESTIMATE algorithm revealed that higher FXYD3 mRNA levels were associated with increased infiltration of immune cells and tumor purity. Moreover, the FXYD3 high KIRC tissue harbored increased TILs such as B cells, CD8+ T cells, and M1 macrophage, whereas NK cells and neutrophils were decreased. In addition, we showed FXYD3 was co-expressed with several immunoinhibitory genes related to T cell exhaustion such as LGALS9, CTLA4, BTLA, PDCD1, and LAG3. In conclusion, FXYD3 is an unfavorable prognostic biomarker associated with hypoxia, pro-tumor TILs, and T cell exhaustion.

International audience; A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFN gamma-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but a high rate of immune-related adverse events (irAE). Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 advanced melanoma patients treated with CICB, with a high rate of any ≥Grade 3 irAEs (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1b in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.

BackgroundProstate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT.MethodsPreclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens.ResultsIn PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so.ConclusionsThese findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.

Objective Forkhead box P3 (FOXP3) is a master transcriptional factor of regulatory T-cells (Tregs). Recent studies have shown that FOXP3 is associated with growth inhibition of cancer cells. However, the role of FOXP3 in acute T-lymphoblastic leukemia (T-ALL) cells is not known. It was also reported that NOTCH signaling promoted the expression of FOXP3 in Tregs. However, the effect of FOXP3 on NOTCH expression in T-ALL cells is little known. Therefore, we examined the effect of FOXP3 knockdown on the proliferation of T-ALL cells and NOTCH1 signaling. Results Two T-ALL cell lines Jurkat and KOPT-K1, harboring activating NOTCH1 mutations, were transfected with small interfering RNA against FOXP3. Cell growth was assessed with a colorimetric assay and morphology was observed under a microscope. FOXP3 knockdown significantly reduced cell growth and induced morphological changes suggesting apoptosis. Quantitative polymerase chain reaction revealed that FOXP3 knockdown caused the downregulation of mRNA expression of NOTCH1 and HES1. These findings suggest that FOXP3 supports the growth of T-ALL cells although this can not be generalized because we examined only two cell lines. The observed growth suppression can be partly due to the downregulation of NOTCH1 signaling. FOXP3 may be a potential therapeutic target in T-ALL.

We report a case of head injury with posterior reversible encephalopathy syndrome (PRES), followed by Guillain-Barré syndrome (GBS). A 74-year-old man was brought to our hospital after a fall. Computed tomography revealed intracranial hemorrhage. Magnetic resonance imaging showed bilateral reversible intensities with features of vasogenic edema in parietooccipital areas, suggesting PRES. After admission, weakness and areflexia of extremities and respiratory muscles developed gradually, which favored a diagnosis of GBS. Common etiologies of PRES were absent. Concurrent occurrence of PRES and GBS is rare. Given that PRES can be an initial manifestation of GBS, GBS must be considered in head trauma patients with PRES.

Immunosurveillance plays an important role in breast cancer (BC) prognosis and progression, and can be geared by immunogenic chemotherapy. In a cohort of 1023 BC patients treated with neoadjuvant chemotherapy (NAC), 40% of the individuals took comedications mostly linked to aging and comorbidities. We systematically analyzed the off-target effects of 1178 concurrent comedications (classified according to the Anatomical Therapeutic Chemical (ATC) Classification System) on the density of tumor-infiltrating lymphocytes (TILs) and pathological complete responses (pCR). At level 1 of the ATC system, the main anatomical classes of drugs were those targeting the nervous system (class N, 39.1%), cardiovascular disorders (class C, 26.6%), alimentary and metabolism (class A, 16.9%), or hormonal preparations (class H, 6.5%). At level 2, the most frequent therapeutic classes were psycholeptics (N05), analgesics (N02), and psychoanaleptics (N06). Pre-NAC TIL density in triple-negative BC (TNBC) was influenced by medications from class H, N, and A, while TIL density in HER2+ BC was associated with the use of class C. Psycholeptics (N05) and agents acting on the renin-angiotensin system (C09) were independently associated with pCR in the whole population of BC or TNBC, and in HER2-positive BC, respectively. Importantly, level 3 hypnotics (N05C) alone were able to reduce tumor growth in BC bearing mice and increased the anti-cancer activity of cyclophosphamide in a T cell-dependent manner. These findings prompt for further exploration of drugs interactions in cancer, and for prospective drug-repositioning strategies to improve the efficacy of NAC in BC.

Synovial osteochondromatosis (SOC) is a benign tumor characterized by synovial connective tissue metaplasia. SOC commonly affects major joints including the knee followed by the hip, elbow, and wrist. SOC cases in the hand are not reported as often as SOC of major joints. Particularly SOC of the carpometacarpal joint of the thumb is rare. We report on a 57-year-old female with primary SOC of the carpometacarpal joint of her left thumb. Surgical excision was performed and the patient had no symptoms with full range of motion of her left thumb. At 3 years of follow-up, there was no recurrence.

In Japanese patients with non-muscle-invasive urothelial carcinoma of the bladder, the impact of body mass index (BMI) on recurrence following transurethral resection of bladder tumor (TURBT) is unclear. The present study retrospectively examined data collected from 50 patients diagnosed with primary urothelial carcinoma of the bladder (pTa, pTis, and pT1) who had previously undergone TURBT surgery. Two BMI cut-off points for predicting disease recurrence were evaluated: i) A threshold generated through receiver operating characteristic (ROC) curve analysis; ii) the World Health Organization BMI index (24 kg/m2) for overweight status in Japanese populations. Univariate and multivariate analyses were applied to assess individual variables (BMI included) and the effect they had on recurrence-free survival (RFS). Median RFS and BMI values of 19.72 months (range, 3.13–72.13 months) and 23.37 kg/m2 (range, 14.72–36.84 kg/m2), respectively, were recorded. In multivariate analyses, higher continuous BMI was significantly associated with shorter RFS (P=0.019). Based on a ROC-generated BMI cut-off point (23.4 kg/m2), patients were ranked with either a high (≥23.4 kg/m2) or low (23.4 kg/m2 were significantly associated with shorter RFS (P=0.028). Intravesical Bacillus Calmette-Guérin treatment and history of upper-tract urothelial carcinoma were also independently associated (P=0.044 and P=0.010, respectively). However, BMI values >24 kg/m2 (customary cut-off point) had no significant impact on RFS (P=0.066). Thus, a higher BMI status was revealed to be independently predictive of shorter RFS in Japanese patients undergoing TURBT for urothelial carcinoma of the bladder. A greater number of samples are required in order to determine optimal BMI cut-off points in Japanese patients and to investigate whether weight reduction intervention may improve prognosis.

The aim of this study is to investigate the role of androgen receptor (AR) expression on clinicopathologic characteristics, first recurrence free survival (RFS), progression free survival (PFS) and multiple recurrences in non-muscle invasive bladder cancer (NMIBC). AR expression in 40 paraffin-embedded specimens of primarily diagnosed NMIBC after transurethral resection was examined by immunohistochemistry using a monoclonal AR antibody. Associations between AR expression and clinicopathologic features and prognosis were statistically assessed. Multivariate Cox proportional hazards model was applied for evaluating predictive factors on RFS and PFS. For multiple recurrences, we used the Andersen-Gill model. AR was positive in 20/40 (50%) cases. Twenty-three patients (57.5%) had no recurrence, 10 (25.0%) had one recurrence, and 7 (17.5%) experienced more than one recurrence. AR expression and clinicopathologic features were not significantly correlated (P >0.05). Univariate analyses showed that AR expression was significantly associated with RFS and PFS (P

We have studied nuclear reaction during a fracture process of piezoelectric materials in D2 atmosphere. Neutrons are generated in d–d nuclear reaction through the fracture process of LiNbO3 (lithium niobate) at the D2 gas pressure of 30 kPa or above; the emission rate is 108±27 /h with the statistical significance of 4.0 σ, although at 18 kPa or below, neutrons are not generated. We have not observed neutrons from other tested piezoelectric materials.

To examine the effects of echinomycin, a compound that inhibits DNA-binding activity of hypoxia-inducible factor-1 (HIF1), on leukaemia cell growth.Three acute myeloid leukaemia cell lines and three T-lymphoblastic leukaemia cell lines were cultured with echinomycin. Cell growth, mRNA and protein expression levels were examined by WST-1 assay, reverse-transcription polymerase chain reaction and immunoblotting, respectively.HIF1α protein was expressed in all cell lines under normoxia. Treatment with echinomycin suppressed cell growth and induced apoptosis in association with decreased mRNA expression of HIF1 targets, glucose transporter-1 (GLUT1) and B-cell CLL/lymphoma-2 (BCL2). Echinomycin also suppressed the protein expression of NOTCH1, cleaved NOTCH1, v-myc myelocytomatosis viral oncogene homolog (MYC), v-akt murine thymoma viral oncogene homolog-1 (AKT), phosphorylated AKT, mechanistic target of rapamycin (mTOR), and phosphorylated mTOR and increased that of cleaved caspase-3 in some cell lines.Echinomycin suppresses leukaemia cell growth in association with reduced NOTCH1 expression. This is the first report to show that HIF inhibitor treatment suppresses NOTCH1 signalling. HIF inhibitors could be novel candidates for a molecular-targeted therapy against leukaemia.