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Theobromine (or 3,7-dimethylxanthine) is a natural alkaloid present in cocoa plant and its derivatives, such as chocolate. About 20% of ingested theobromine is excreted unchanged in the urine. Theobromine also derived from caffeine that is metabolized into theobromine by 12%. The primary metabolites of theobromine are 3-methylxantine, 7-methylxantine, 7-methyluric acid and 3,7-dimethyluric acid. Theobromine has an inhibitory activity of uric acid crystallization, because it has a structural pattern very similar to uric acid and can substitute uric acid molecules in the corresponding uric acid crystals, making them longer and thinner and decreasing their growth rate. Theobromine also favors the dissolution of crystals by decreasing supersaturation of uric acid by forming aggregates with uric acid through hydrogen bonds and aromatic stacking interactions (-stacking bonds) increasing urinary solubility of uric acid. Theobromine can be used for uric acid stone dissolution in combination with alkalinization to reduce the dose of citrate, thus preventing excessive alkalinization and the risk of formation of sodium urate crystals. Theobromine could also be used to treat patient with xanthine stones that cannot be dissolved by alkalinization because the solubility of xanthine is relatively independent of urinary pH. A metabolite of theobromine, 7-methylxanthine, has the potential to be used for the prevention of the formation of sodium urate crystals in the synovial fluid of gouty patients.

Abstract Change within the intratumoral microbiome is a common feature in lung and other cancers and may influence inflammation and immunity in the tumor microenvironment, affecting growth and metastases. We previously characterized the lung cancer microbiome in patients and identified Acidovorax temperans as enriched in tumors. Here, we instilled A. temperans in an animal model driven by mutant K-ras and Tp53. This revealed A. temperans accelerates tumor development and burden through infiltration of proinflammatory cells. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic phenotype with increased cytokine signaling, with a global shift away from IL-1β signaling. Neutrophil to monocyte and macrophage signaling upregulated MHC II to activate CD4+ T cells, polarizing them to an IL-17A+ phenotype detectable in CD4+ and γδ populations (T17). These T17 cells shared a common gene expression program predictive of poor survival in human LUAD. These data indicate bacterial exposure promotes tumor growth by modulating inflammation.

Abstract Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.

Introduction: 5-phosphodiesterase inhibitors (PDE-5I) have been investigated as a treatment for urinary dysfunction for almost a decade. The general perception is that they play a significant role in managing lower urinary tract symptoms (LUTS), particularly those associated with benign prostatic hyperplasia (BPH). However, the specific biochemical processes by which PDE-5I repairs urinary function are still poorly understood and there is little instrumental evidence of significant improvement in urinary symptoms. Therefore, we explore the role of 5-phosphodiesterase inhibitors (PDE-5I) as complementary to the conventional treatment of symptomatic BPH; we provide the suggested biological procedures involved in the association between PDE-5 inhibitor use and improvement in LUTS; and we propose new approaches to this topic. Material and Methods: A systematic search for clinical trials, experimental studies, and systematic reviews was performed in electronic libraries (PubMed, EMBASE, Scopus) using the terms “benign prostate hypertrophy”, “benign prostate hyperplasia”, “lower urinary tract symptoms”, “storage symptoms”, “voiding symptoms”, “bladder outlet obstruction” and the keywords “mechanism of action”, “synergy”, “PDE-5 inhibitor”, “alpha1-adrenergic antagonist”, “5-alpha-reductase inhibitors” in various combinations. There was no restriction on publication date. Results: To date, only a few randomized studies have been published in which the effect of the combination of a conventional drug for the treatment of symptomatic BPH and a PDE-5I was investigated. Almost all showed significant improvement in IPSS and QoL. Some studies showed significant improvements in maximum urine flow (Qmax) and postvoiding residual volume (PVR) with combination therapy compared with a single agent alone. Conclusions: PDE-5I seems effective in relieving symptoms of some BPH patients when administered as complementary to agents currently used to treat BPH. However, the mechanism of action of PDE-5 inhibitors in LUTS remains poorly understood and it is difficult to determine the specific subset of BPH patients who will benefit from the combination of PDE-5 inhibitors with the current treatment. Well-designed, sufficiently informative comparative studies focusing on specific target group profiles (age, urogenital parameters) are needed to define new therapeutic options.

Unique gut microbiota compositions have been associated with inflammatory diseases, but identifying gut bacterial functions linked to immune activation in humans remains challenging. Translocation of pathogens from mucosal surfaces into peripheral tissues can elicit immune activation, although whether and which gut commensal bacteria translocate in inflammatory diseases is difficult to assess. We report that a subset of commensal gut microbiota constituents that translocate across the gut barrier in mice and humans are associated with heightened systemic immunoglobulin G (IgG) responses. We present a modified high-throughput, culture-independent approach to quantify systemic IgG against gut commensal bacteria in human serum samples without the need for paired stool samples. Using this approach, we highlight several commensal bacterial species that elicit elevated IgG responses in patients with inflammatory bowel disease (IBD) including taxa within the clades Collinsella, Bifidobacterium, Lachnospiraceae, and Ruminococcaceae. These and other taxa identified as translocating bacteria or targets of systemic immunity in IBD concomitantly exhibited heightened transcriptional activity and growth rates in IBD patient gut microbiomes. Our approach represents a complementary tool to illuminate interactions between the host and its gut microbiota and may provide an additional method to identify microbes linked to inflammatory disease.

Purpose: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is characterized by a multiform clinical presentation requiring a differentiated treatment based on different phenotypes including the psychosocial and sexual domains. The aim of this study was assessing the complex correlations between somatic, psychological, and sexual symptoms of CP/CPPS patients. Materials and methods: We performed a cross-sectional study on patients attending a Prostatitis Clinic. Patients were administered the following questionnaires: National Institutes of Health- Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF), Premature Ejaculation Diagnostic Tool (PEDT), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7-item (GAD-7), Oxford Happiness Questionnaire (OHQ), and Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A). Results: Linear regression analyses show highly significant correlations between scores of the NIH-CPSI and the scores of the GAD-7, PHQ-9 and OHQ psychometric questionnaires. IPSS scores correlate significantly with the psychometric scores only when a non-parametric analysis is performed. IIEF and PEDT sexual function scores did not correlate with any of the psychometric tests. NIH-CPSI scores correlate positively with most of the TEMPS-A profiles but the hyperthymic profile correlated negatively with the total and QoL NIH-CPSI and with PEDT scores. Conclusions: Scores measuring anxiety, depression, and psychological well-being in patients with CP/CPPS are strictly correlated with prostatitis-like symptoms although they are poorly correlated with symptoms of prostatism, as measured by IPSS, and not correlated with scores of sexual dysfunctions, as measured by IIEF and PEDT. A hyperthymic temperament may increase resilience against the disease.

Aim: To present state of the art on the management of urinary stones from a panel of globally recognized urolithiasis experts who met during the Experts in Stone Disease Congress in Valencia in January 2024. Options of treatment: The surgical treatment modalities of renal and ureteral stones are well defined by the guidelines of international societies, although for some index cases more alternative options are possible. For 1.5 cm renal stones, both m-PCNL and RIRS have proven to be valid treatment alternatives with comparable stone-free rates. The m-PCNL has proven to be more cost effective and requires a shorter operative time, while the RIRS has demonstrated lower morbidity in terms of blood loss and shorter recovery times. SWL has proven to be less effective at least for lower calyceal stones but has the highest safety profile. For a 6mm obstructing stone of the pelviureteric junction (PUJ) stone, SWL should be the first choice for a stone less than 1 cm, due to less invasiveness and lower risk of complications although it has a lower stone free-rate. RIRS has advantages in certain conditions such as anticoagulant treatment, obesity, or body deformity. Technical issues of the surgical procedures for stone removal: In patients receiving antithrombotic therapy, SWL, PCN and open surgery are at elevated risk of hemorrhage or perinephric hematoma. URS, is associated with less morbidity in these cases. An individualized combined evaluation of risks of bleeding and thromboembolism should determine the perioperative thromboprophylactic strategy. Pre-interventional urine culture and antibiotic therapy are mandatory although UTI treatment is becoming more challenging due to increasing resistance to routinely applied antibiotics. The use of an intrarenal urine culture and stone culture is recommended to adapt antibiotic therapy in case of postoperative infectious complications. Measurements of temperature and pressure during RIRS are vital for ensuring patient safety and optimizing surgical outcomes although techniques of measurements and methods for data analysis are still to be refined. Ureteral stents were improved by the development of new biomaterials, new coatings, and new stent designs. Topics of current research are the development of drug eluting and bioresorbable stents. Complications of endoscopic treatment: PCNL is considered the most invasive surgical option. Fever and sepsis were observed in 11 and 0.5% and need for transfusion and embolization for bleeding in 7 and 0.4%. Major complications, as colonic, splenic, liver, gall bladder and bowel injuries are quite rare but are associated with significant morbidity. Ureteroscopy causes less complications, although some of them can be severe. They depend on high pressure in the urinary tract (sepsis or renal bleeding) or application of excessive force to the urinary tract (ureteral avulsion or stricture). Diagnostic work up: Genetic testing consents the diagnosis of monogenetic conditions causing stones. It should be carried out in children and in selected adults. In adults, monogenetic diseases can be diagnosed by systematic genetic testing in no more than 4%, when cystinuria, APRT deficiency, and xanthinuria are excluded. A reliable stone analysis by infrared spectroscopy or X-ray diffraction is mandatory and should be associated to examination of the stone under a stereomicroscope. The analysis of digital images of stones by deep convolutional neural networks in dry laboratory or during endoscopic examination could allow the classification of stones based on their color and texture. Scanning electron microscopy (SEM) in association with energy dispersive spectrometry (EDS) is another fundamental research tool for the study of kidney stones. The combination of metagenomic analysis using Next Generation Sequencing (NGS) techniques and the enhanced quantitative urine culture (EQUC) protocol can be used to evaluate the urobiome of renal stone formers. Twenty-four hour urine analysis has a place during patient evaluation together with repeated measurements of urinary pH with a digital pH meter. Urinary supersaturation is the most comprehensive physicochemical risk factor employed in urolithiasis research. Urinary macromolecules can act as both promoters or inhibitors of stone formation depending on the chemical composition of urine in which they are operating. At the moment, there are no clinical applications of macromolecules in stone management or prophylaxis. Patients should be evaluated for the association with systemic pathologies. Prophylaxis: Personalized medicine and public health interventions are complementary to prevent stone recurrence. Personalized medicine addresses a small part of stone patients with a high risk of recurrence and systemic complications requiring specific dietary and pharmacological treatment to prevent stone recurrence and complications of associated systemic diseases. The more numerous subjects who form one or a few stones during their entire lifespan should be treated by modifications of diet and lifestyle. Primary prevention by public health interventions is advisable to reduce prevalence of stones in the general population. Renal stone formers at "high-risk" for recurrence need early diagnosis to start specific treatment. Stone analysis allows the identification of most “high-risk” patients forming non-calcium stones: infection stones (struvite), uric acid and urates, cystine and other rare stones (dihydroxyadenine, xanthine). Patients at “high-risk” forming calcium stones require a more difficult diagnosis by clinical and laboratory evaluation. Particularly, patients with cystinuria and primary hyperoxaluria should be actively searched. Future research: Application of Artificial Intelligence are promising for automated identification of ureteral stones on CT imaging, prediction of stone composition and 24-hour urinary risk factors by demographics and clinical parameters, assessment of stone composition by evaluation of endoscopic images and prediction of outcomes of stone treatments. The synergy between urologists, nephrologists, and scientists in basic kidney stone research will enhance the depth and breadth of investigations, leading to a more comprehensive understanding of kidney stone formation.

Abstract Clinical and preclinical studies established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) but molecular underpinnings of this action were elusive. Herein, we used multi‐omic network analysis that unveiled critical molecular pathways involved in ω3 PUFA effects in a preclinical mouse model of western diet induced NASH. Since NASH is a precursor of liver cancer, we also performed meta‐analysis of human liver cancer transcriptomes that uncovered betacellulin as a key EGFR‐binding protein upregulated in liver cancer and downregulated by ω3 PUFAs in animals and humans with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, inducing transforming growth factor–β2 and increasing collagen production. When used in combination with TLR2/4 agonists, betacellulin upregulated integrins in macrophages thereby potentiating inflammation and fibrosis. Taken together, our results suggest that suppression of betacellulin is one of the key mechanisms associated with anti‐inflammatory and anti‐fibrotic effects of ω3 PUFA on NASH.

Abstract Background Cachexia is a wasting syndrome associated with systemic inflammation and metabolic disruption. Detection of the early signs of the disease may contribute to the effective attenuation of associated symptoms. Despite playing a central role in the control of metabolism and inflammation, the liver has received little attention in cachexia. We previously described relevant disruption of metabolic pathways in the organ in an animal model of cachexia, and herein, we adopt the same model to investigate temporal onset of inflammation in the liver. The aim was thus to study inflammation in rodent liver in the well‐characterized cachexia model of Walker 256 carcinosarcoma and, in addition, to describe inflammatory alterations in the liver of one cachectic colon cancer patient, as compared to one control and one weight‐stable cancer patient. Methods Colon cancer patients (one weight stable [WSC] and one cachectic [CC]) and one patient undergoing surgery for cholelithiasis (control, n = 1) were enrolled in the study, after obtainment of fully informed consent. Eight‐week‐old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2 × 107 cells in 1.0 mL; tumour‐bearing [T]; or phosphate‐buffered saline—controls [C]). The liver was excised on Days 0 (n = 5), 7 (n = 5) and 14 (n = 5) after tumour cell injection. Results In rodent cachexia, we found progressively higher numbers of CD68+ myeloid cells in the liver along cancer‐cachexia development. Similar findings are described for CC, whose liver showed infiltration of the same cell type, compared with both WSC and control patient organs. In advanced rodent cachexia, hepatic phosphorylated c‐Jun N‐terminal kinase protein content and the inflammasome pathway protein expression were increased in relation to baseline (P

Abstract Background Formyl peptide receptor 2 (Fpr2) plays a crucial role in colon homeostasis and microbiota balance. Commensal E. coli is known to promote the regeneration of damaged colon epithelial cells. The aim of the study was to investigate the connection between E. coli and Fpr2 in the recovery of colon epithelial cells. Results The deficiency of Fpr2 was associated with impaired integrity of the colon mucosa and an imbalance of microbiota, characterized by the enrichment of Proteobacteria in the colon. Two serotypes of E. coli, O22:H8 and O91:H21, were identified in the mouse colon through complete genome sequencing. E. coli O22:H8 was found to be prevalent in the gut of mice and exhibited lower virulence compared to O91:H21. Germ-free (GF) mice that were pre-orally inoculated with E. coli O22:H8 showed reduced susceptibility to chemically induced colitis, increased proliferation of epithelial cells, and improved mouse survival. Following infection with E. coli O22:H8, the expression of Fpr2 in colon epithelial cells was upregulated, and the products derived from E. coli O22:H8 induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency increased susceptibility to chemically induced colitis, delayed the repair of damaged colon epithelial cells, and heightened inflammatory responses. Additionally, the population of E. coli was observed to increase in the colons of Fpr2 −/− mice with colitis. Conclusion Commensal E. coli O22:H8 stimulated the upregulation of Fpr2 expression in colon epithelial cells, and the products from E. coli induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency led to an increased E. coli population in the colon and delayed recovery of damaged colon epithelial cells in mice with colitis. Therefore, Fpr2 is essential for the effects of commensal E. coli on colon epithelial cell recovery.

Background: The prevalence of kidney stones tends to increase worldwide due to dietary and climate changes. Disease management involves a high consumption of healthcare system resources which can be reduced with primary prevention measures and prophylaxis of recurrences. In this field, collaboration between general practitioners (GPs) and hospitals is crucial. Methods: a panel composed of general practitioners and academic and hospital clinicians expert in the treatment of urinary stones met with the aim of identifying the activities that require the participation of the GP in the management process of the kidney stone patient. Results: Collaboration between GP and hospital was found crucial in the treatment of renal colic and its infectious complications, expulsive treatment of ureteral stones, chemolysis of uric acid stones, long-term follow-up after active treatment of urinary stones, prevention of recurrence and primary prevention in the general population. Conclusions: The role of the GP is crucial in the management and prevention of urinary stones. Community hospitals which are normally led by GPs in liaison with consultants and other health professional can have a role in assisting multidisciplinary working as extended primary care.

The triggering receptor expressed on myeloid cell 1 (TREM1) plays a critical role in development of chronic inflammatory disorders and the inflamed tumor microenvironment (TME) associated with most solid tumors. We examined whether loss of TREM1 signaling can abrogate the immunosuppressive TME and enhance cancer immunity. To investigate the therapeutic potential of TREM1 in cancer, we used mice deficient in Trem1 and developed a novel small molecule TREM1 inhibitor, VJDT. We demonstrated that genetic or pharmacological TREM1 silencing significantly delayed tumor growth in murine melanoma (B16F10) and fibrosarcoma (MCA205) models. Single-cell RNA-Seq combined with functional assays during TREM1 deficiency revealed decreased immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) accompanied by expansion in cytotoxic CD8+ T cells and increased PD-1 expression. Furthermore, TREM1 inhibition enhanced the antitumorigenic effect of anti-PD-1 treatment, in part, by limiting MDSC frequency and abrogating T cell exhaustion. In patient-derived melanoma xenograft tumors, treatment with VJDT downregulated key oncogenic signaling pathways involved in cell proliferation, migration, and survival. Our work highlights the role of TREM1 in cancer progression, both intrinsically expressed in cancer cells and extrinsically in the TME. Thus, targeting TREM1 to modify an immunosuppressive TME and improve efficacy of immune checkpoint therapy represents what we believe to be a promising therapeutic approach to cancer.

Background: Urinary incontinence and other urinary symptoms tend to be frequent at menopause because of hormonal modifications and aging. Urinary symptoms are associated with the genitourinary syndrome of menopause which is characterized by physical changes of the vulva, vagina and lower urinary tract. The treatment strategies for postmenopausal urinary incontinence are various and may include estrogens, anticholinergics, and pelvic floor muscle training. A comparison of these treatments is difficult due to the heterogeneity of adopted protocols. We systematically reviewed the evidence from randomized controlled trials (RCTs) focusing on treatment of postmenopausal women with urge incontinence. Methods: We conducted a systematic review and meta-analysis by searching PubMed and EMBASE databases for randomized controlled trials (RCTs) reporting results of treatments for postmenopausal urinary urge incontinence. Odds ratios for improvement of urinary incontinence were calculated using random effect Mantel-Haenszel statistics. Results: Out of 248 records retrieved, 35 eligible RCTs were assessed for risk of bias and included in the meta-analysis. Compared with placebo, systemic estrogens were associated with decreased odds of improving urinary incontinence in postmenopausal women (OR = 0.74, 95% CI: 0.61-0.91, 7 series, 17132 participants, Z = 2.89, P = 0.004, I2 = 72%). In most studies, no significant improvement in urinary symptoms was observed in patients treated with local estrogens, although they showed to be helpful in improving vaginal symptoms. Vitamin D, phytoestrogens and estrogen modulators were not effective in improving symptoms of incontinence and other symptoms of genitourinary menopause syndrome or yielded contradictory results. A randomized controlled trial demonstrated that oxybutynin was significantly better than placebo at improving postmenopausal urgency and urge incontinence. The combination of anticholinergics with local estrogens has not been shown to be more effective than anticholinergics alone in improving urinary incontinence symptoms in postmenopausal women. Physical therapy showed an overall positive outcome on postmenopausal urinary incontinence symptoms, although such evidence should be further validated in the frame of quality RCTs. Conclusions: The evidence for effective treatment of postmenopausal urinary incontinence is still lacking. Welldesigned large studies having subjective and objective improvement primary endpoints in postmenopausal urinary incontinence are needed. At present, a combination of different treatments tailored to the characteristics of the individual patient can be suggested.

As part of the 2019 Immunotherapy Bridge congress (December 4-5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report.

Low grade, chronic inflammation is a critical risk factor for immunologic dysfunction including autoimmune diseases. However, the multiplicity of complex mechanisms and lack of relevant murine models limit our understanding of the precise role of chronic inflammation. To address these hurdles, we took advantage of multi-omics data and a unique murine model with a low but chronic expression of IFN-γ, generated by replacement of the AU-rich element (ARE) in the 3' UTR region of IFN-γ mRNA with random nucleotides. Herein, we demonstrate that low but differential expression of IFN-γ in mice by homozygous or heterozygous ARE replacement triggers distinctive gut microbial alterations, of which alteration is female-biased with autoimmune-associated microbiota. Metabolomics data indicates that gut microbiota-dependent metabolites have more robust sex-differences than microbiome profiling, particularly those involved in fatty acid oxidation and nuclear receptor signaling. More importantly, homozygous ARE-Del mice have dramatic changes in tryptophan metabolism, bile acid and long-chain lipid metabolism, which interact with gut microbiota and nuclear receptor signaling similarly with sex-dependent metabolites. Consistent with these findings, nuclear receptor signaling, encompassing molecules such as PPARs, FXR, and LXRs, was detectable as a top canonical pathway in comparison of blood and tissue-specific gene expression between female homozygous vs heterozygous ARE-Del mice. Further analysis implies that dysregulated autophagy in macrophages is critical for breaking self-tolerance and gut homeostasis, while pathways interact with nuclear receptor signaling to regulate inflammatory responses. Overall, pathway-based integration of multi-omics data provides systemic and cellular insights about how chronic inflammation driven by IFN-γ results in the development of autoimmune diseases with specific etiopathological features.

The triggering receptor expressed on myeloid cell 1 (TREM1) plays a critical role in development of chronic inflammatory disorders and the inflamed tumor microenvironment (TME) associated with most solid tumors. We examined whether loss of TREM1 signaling can abrogate the immunosuppressive TME and enhance cancer immunity. To investigate the therapeutic potential of TREM1 in cancer, we used mice deficient in Trem1 and developed a novel small molecule TREM1 inhibitor, VJDT. We demonstrated that genetic or pharmacological TREM1 silencing significantly delayed tumor growth in murine melanoma (B16F10) and fibrosarcoma (MCA205) models. Single-cell RNA-Seq combined with functional assays during TREM1 deficiency revealed decreased immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) accompanied by expansion in cytotoxic [CD8.sup.+] T cells and increased PD-1 expression. Furthermore, TREM1 inhibition enhanced the antitumorigenic effect of anti-PD-1 treatment, in part, by limiting MDSC frequency and abrogating T cell exhaustion. In patient-derived melanoma xenograft tumors, treatment with VJDT downregulated key oncogenic signaling pathways involved in cell proliferation, migration, and survival. Our work highlights the role of TREM1 in cancer progression, both intrinsically expressed in cancer cells and extrinsically in the TME. Thus, targeting TREM1 to modify an immunosuppressive TME and improve efficacy of immune checkpoint therapy represents what we believe to be a promising therapeutic approach to cancer., Introduction Triggering receptor expressed on myeloid cell 1 (TREM1) is a cell surface receptor and a member of the immunoglobulin superfamily that amplifies inflammatory responses by inducing the secretion of [...]

BackgroundNonalcoholic fatty liver disease (NAFLD) is a global health problem. Identifying early gene indicators contributing to the onset and progression of NAFLD has the potential to develop novel targets for early therapeutic intervention. We report on the early and late transcriptomic signatures of western diet (WD)-induced nonalcoholic steatohepatitis (NASH) in female and male Ldlr−/− mice, with time-points at 1 week and 40 weeks on the WD. Control Ldlr−/− mice were maintained on a low-fat diet (LFD) for 1 and 40 weeks.MethodsThe approach included quantitation of anthropometric and hepatic histology markers of disease as well as the hepatic transcriptome.ResultsOnly mice fed the WD for 40 weeks revealed evidence of NASH, i.e., hepatic steatosis and fibrosis. RNASeq transcriptome analysis, however, revealed multiple cell-specific changes in gene expression after 1 week that persisted to 40 weeks on the WD. These early markers of disease include induction of acute phase response (Saa1-2, Orm2), fibrosis (Col1A1, Col1A2, TGFβ) and NASH associated macrophage (NAM, i.e., Trem2 high, Mmp12 low). We also noted the induction of transcripts associated with metabolic syndrome, including Mmp12, Trem2, Gpnmb, Lgals3 and Lpl. Finally, 1 week of WD feeding was sufficient to significantly induce TNFα, a cytokine involved in both hepatic and systemic inflammation.ConclusionThis study revealed early onset changes in the hepatic transcriptome that develop well before any anthropometric or histological evidence of NALFD or NASH and pointed to cell-specific targeting for the prevention of disease progression.

Introduction/Aim: A spectrum of psychological problems is commonly found in CP/CPPS patients, though it is not yet clear whether, a priori, psychological dysfunctions are the cause of these pain syndromes, or whether these pain conditions are themselves causing psychological disturbances. In this article we present the current perspective on the impact of psychological problems in chronic prostatitis syndromes and we discuss the implications thereof from a clinical perspective. Materials and Methods: A database and a manual search were conducted in the MEDLINE database of the National Library of Medicine, EMBASE, and other libraries using the key words “prostatitis syndromes”, “chronic bacterial prostatitis”, “chronic pelvic pain”, in various combinations with the terms “psychological issues”, “depression” “anxiety”, “stress”, “unhappiness”, “cognitive status” and “personality”. Two independent reviewers performed data extraction. We included clinical studies with available information on chronic prostatitis and related psychological conditions. We considered full-text written papers. We excluded reviews and case reports. In order to reduce the risk of bias we analyzed only studies including patients with confirmed CBP or CP/CPPS. Bibliographic information in the selected publications was checked for relevant records not included in the initial search. Results: Database search allowed us to retrieve 638 studies to which we added to 16 additional studies retrieved by hand-searching. After screening, 34 relevant papers were identified for thorough review. Most studies included patients with chronic pelvic pain and prostatitis-like symptoms, whereas a smaller number of studies included patients with methodologically con- firmed CP/CPPS including studies with a microbiologically confirmed diagnosis of CBP. The psychosocial factors examined in the selected studies include pain, catastrophizing, stress, personality factors and social aspects. Comorbid psychiatric disorders evidenced in the studies included depression, anxiety and trauma-related disorders, somatization disorders, and substance abuse. Some studies investigated the association of pain with each individual psychological disturbance, while others examined the impact of pain in association with the overall quality of life. Sample size, study design and diagnostic measures varied among studies. Conclusions: Despite limitations and variations in sample size, study design and diagnostic measures in all included studies, a relation between chronic prostatitis and psychological problems is a consistent finding. The existing evidence does not permit to definitely conclude whether psychological problems are a risk factor for CP/CPPS or whether they represent an array of symptoms that are associated with the exacerbation of this disease.