Selective anti-CXCR2 receptor blockade by AZD5069 inhibits CXCL8-mediated pro-tumorigenic activity in human thyroid cancer cells in vitro.

BACKGROUND: Thyroid cancer is the most common endocrine malignancy. Current therapies are successful, however some patients progress to therapeutically refractive disease. The immunotherapeutic potential of the CXCL8-chemokine/CXCR2-chemokine-receptor system is currently being explored in numerous human cancers. This study aimed to evaluate if the targeting of CXCR2 by its selective antagonist, AZD5069, could modulate CXCL8-mediated pro-tumorigenic effects in thyroid-cancer (TC) cells in vitro. METHODS: Normal human primary thyroid cells (NHT) and TC cell lines TPC-1 (RET/PTC), BCPAP, 8505C and 8305C (BRAFV600e) were treated with AZD5069 (100 pM-10 µM) over a time-course. Viability and proliferation were assessed by WST-1 and crystal violet assays. CXCL8 and CXCR2 mRNA were evaluated by RT-PCR. CXCL8-protein concentrations were measured in cell culture supernatants by ELISA. CXCR2 on cell surface was evaluated by flow-cytometry. Cell-migration was assessed by trans-well-migration chamber-system. RESULTS: AZD5069 exerted negligible effects on cell proliferation or viability. AZD5069 significantly reduced CXCR2, (but not CXCL8) mRNAs in all cell types. CXCR2 was reduced on the membrane of some TC cell lines. A significant reduction of the CXCL8 secretion was found in TPC-1 cells (basal-secretion) and NHT (TNFα-induced secretion). AZD5069 significantly reduced basal and CXCL8-induced migration in NHT and different TC cells. CONCLUSIONS: Our findings confirm the involvement of the CXCL8/CXCR2-axis in promoting pro-tumorigenic effects in TC cells, further demonstrating its immunotherapeutic significance in human cancer.

Laparoscopic adrenalectomy for a giant adrenal myelolipoma: A case report.

CASE PRESENTATION: We describe a case of a patient who presented with a mildly symptomatic, giant myelolipoma which was excised by laparoscopic approach without complications. INTRODUCTION AND IMPORTANCE: Adrenal myelolipoma (AML) is a rare tumour composed by fat and myeloid tissues. Usually it is asymptomatic, so the diagnosis is mostly incidental. It is generally located in the right adrenal gland, but it can also be found bilaterally. If its size exceeds 10 cm it is defined as a "giant myelolipoma"; in this case its treatment of choice would be adrenalectomy with an open surgical approach. CLINICAL DISCUSSION: Patient's signs and symptoms were mild pain in the right hypochondrium and a positive right Giordano's sign. The mass was detected by a contrast-enhanced CT scan. Once excised it measured 16 cm. CONCLUSION: Laparoscopic adrenalectomy for giant myelolipoma is a safe approach if performed by an expert surgeon, with low risk of bleeding and a better outcome for the patient.

Promyelocytic leukemia protein: an atherosclerosis suppressor protein?

As many as 70% of cells in atherosclerotic plaque are vascular smooth muscle cell (VSMC) in origin, and pathways and proteins which regulate VSMC migration, proliferation, and phenotype modulation represent novel targets for rational drug design to reduce atherosclerotic vascular disease. In this volume of Clinical Science, Karle et al. demonstrate that tumor suppressor, promyelocytic leukemia protein (PML) plays an important role in regulation of VSMC phenotype and response to inflammatory stimuli (Clin Sci (2021) 135(7), 887-905; DOI: 10.1042/CS20201399). This important work demonstrates that PML, previously unrecognized as a participant in development of atherosclerosis, may represent a novel target for anti-atherosclerotic therapeutic modalities.

Reward and immune responses in adolescent females following experimental traumatic brain injury.

The pathology of traumatic brain injury (TBI) adversely affects many brain regions, often resulting in the development of comorbid psychiatric disorders including substance use disorders (SUD). Although traditionally thought to be an epidemic that predominantly affects males, recent clinical studies report females have higher rates of concussions and longer recovery times than males. Yet, how neurotrauma, particularly deep within the brain, between the sexes is differentially manifested remains largely unknown. The risk of TBI peaks during adolescence when neuronal networks that regulate reward behaviors are not fully developed. Previously, using the conditioned place preference (CPP) assay, we found that adolescent TBI increased susceptibility to the rewarding effects of cocaine in male mice. Further, we observed augmented inflammatory profiles, increased microglial phagocytosis of neuronal proteins, and decreased neuronal spine density in the NAc. Notably, the extent of sex differences in SUD susceptibility following TBI has not be investigated. Thus, here we ask the central question of whether the adolescent TBI-induced neuroinflammatory profile at reward centers is divergent in a sex-dependent manner. Using the CPP assay, we found that female mice with high levels of female sex hormones at the time of adolescent TBI demonstrated neuroprotection against increased sensitivity to the rewarding effects of cocaine. These studies also provide evidence of significantly reduced microglial activation and phagocytosis of neuronal proteins within the NAc of females. Overall, our results offer crucial insight into how adolescent TBI impacts the reward pathway in a sex depending manner that could explain a vulnerability to addiction-like behavior.

Tuning cancer fate: the unremitting role of host immunity.

Host immunity plays a central and complex role in dictating tumour progression. Solid tumours are commonly infiltrated by a large number of immune cells that dynamically interact with the surrounding microenvironment. At first, innate and adaptive immune cells successfully cooperate to eradicate microcolonies of transformed cells. Concomitantly, surviving tumour clones start to proliferate and harness immune responses by specifically hijacking anti-tumour effector mechanisms and fostering the accumulation of immunosuppressive immune cell subsets at the tumour site. This pliable interplay between immune and malignant cells is a relentless process that has been concisely organized in three different phases: elimination, equilibrium and escape. In this review, we aim to depict the distinct immune cell subsets and immune-mediated responses characterizing the tumour landscape throughout the three interconnected phases. Importantly, the identification of key immune players and molecules involved in the dynamic crosstalk between tumour and immune system has been crucial for the introduction of reliable prognostic factors and effective therapeutic protocols against cancers.

Enhanced recovery after surgery (ERAS) pathway vs traditional care in laparoscopic rectal resection: a single-center experience.

BACKGROUND: The aim of this study was to compare the outcome of an enhanced recovery after surgery (ERAS) pathway with traditional perioperative care in laparoscopic rectal resection. METHODS: A retrospective analysis of prospectively collected data was conducted. Single-center consecutive patients who underwent laparoscopic rectal surgery after an ERAS program were compared with patients who received traditional care over an 8-year period. Primary and total length of stay, and readmission, morbidity and mortality rates were analyzed. For ERAS group, the actual adherence to protocol was also evaluated. RESULTS: Two hundred and ninety-seven patients, 162 in the ERAS group and 135 in conventional care, were studied. Median primary and total length of stay were significantly shorter in the ERAS group (9 vs 12 days; p = 0.0001; 10 vs 12 days; p = 0.01; respectively). The ERAS group experienced a faster recovery of bowel function than the traditional care group (p = 0.0001). A similar morbidity rate was observed in the two groups (32.3 % in ERAS vs 36.1 % in traditional care p = 0.41). Readmission rates were 4.9 % in the ERAS versus 1.5 % in the traditional care group (p = 0.19). There was no mortality in either group. Overall mean compliance with the ERAS protocol was 85.7 % (range 54.4-100 %). CONCLUSIONS: The introduction of the ERAS protocol in laparoscopic rectal resection led to a reduction in primary and total length of hospital stay without an increase in morbidity or readmission rates when compared to traditional care.

Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1.

Mesenchymal stem cells (MSC) represent a promising therapeutic approach in many diseases in view of their potent immunomodulatory properties, which are only partially understood. Here, we show that the endothelium is a specific and key target of MSC during immunity and inflammation. In mice, MSC inhibit activation and proliferation of endothelial cells in remote inflamed lymph nodes (LNs), affect elongation and arborization of high endothelial venules (HEVs) and inhibit T-cell homing. The proteomic analysis of the MSC secretome identified the tissue inhibitor of metalloproteinase-1 (TIMP-1) as a potential effector molecule responsible for the anti-angiogenic properties of MSC. Both in vitro and in vivo, TIMP-1 activity is responsible for the anti-angiogenic effects of MSC, and increasing TIMP-1 concentrations delivered by an Adeno Associated Virus (AAV) vector recapitulates the effects of MSC transplantation on draining LNs. Thus, this study discovers a new and highly efficient general mechanism through which MSC tune down immunity and inflammation, identifies TIMP-1 as a novel biomarker of MSC-based therapy and opens the gate to new therapeutic approaches of inflammatory diseases.

Comparison of standard polyethylene glycol and two doses of oral sodium phosphate solution in precolonoscopy bowel preparation: a randomized controlled trial.

BACKGROUND AND STUDY AIMS: This study was undertaken to compare the efficacy, side effects and patient acceptance of standard 4-liters polyethylene glycol (PEG) and 2 doses of sodium phosphate (NaP) solution for precolonoscopy colon cleansing. PATIENTS AND METHODS: A total of 182 patients were randomized to receive either standard 4-L PEG (88 patients) or 80 mL of NaP (94 patients) in a split regimen of two 40 mL doses separated by 24 h, prior to colonoscopic evaluation. The primary endpoint was the segmental assessment of colonic wall visualization. Secondary outcomes included percent of assumed preparation, and the patient tolerance and acceptability. RESULTS: A significantly higher completion rate was found in the NaP group compared to the PEG group (84.3% vs 62.9%; difference, 21.40%; 95% confidence interval [CI], 8.29% to 34.51%; p = 0.001). PEG solution caused more nausea than NaP solution (p = 0.024). Patient acceptance for bowel preparation with NaP was greater (p = 0.019). Adequate colon wall visualization was achieved in similar proportion of patients in both groups with exception of the descending colon, where NaP regimen was superior (72.0% vs 52.9%; difference, 19.10%; 95% CI, 5.20% to 33.00% ; p = 0.012). CONCLUSIONS: Two doses of NaP solution, taken 24 h and 12 h before colonoscopy, tend to guarantee superior results in colonic cleansing with respect to standard 4-liters PEG solution. Taking the second dose of NaP 24 h after the first dose reduces side effects and allows achieving a more satisfactory compliance of the patient.

Spontaneous ruptured pheochromocytoma: a case report.

We present a rare case of intra-abdominal hemorrhage due to a ruptured pheochromocytoma. Our patient presented with signs of shock. By emergency surgery, an hemorrhagic pheochromocytoma of the left adrenal gland was removed. Recovery was uneventful. In cases of suspected hemorrhagic pheochromocytoma with severe shock, prompt surgery is mandatory and catecholamines administration may be crucial to resolve hypotension and guarantee an uneventful recovery.

[Massive lower gastrointestinal bleeding due to diverticular disease during antiplatelet therapy. Case report]. / Enterorragia massiva da diverticolosi sigmoidea in corso di terapia antiaggregante. Caso clinico.

Diverticular disease is very frequent in Western countries; in 5% of the cases it is the cause of serious bleeding, haemodynamic instability and death. The authors report a case of 74 years old patient with severe lower gastrointestinal bleeding. She was in antiplatelet treatment with acetylsalicylic acid (100 mg/die) and clopidogrel (75 mg/die) for preventing the restenosis of medicated stents positioned to treat an acute coronary syndrome. At the same time the patient was under treatment for primary hypercholesterolemia with rosuvastatin (20 mg/die). The severe haemorrhage demanded haemodynamic stabilization, achieved by colloid infusion and blood transfusions. The bleeding continued; selective arteriography showed it's origin from the areas of the sigmoid and superior hemorrhoidal arteries. During the procedure, embolization of the inferior mesenteric artery using spiral type BALT was performed, with consequent bleeding interruption. Fifteen days after the embolization, a rectosigmoid colonoscopy showed a sigmoid diverticular disease. The treatment with acetylsalicylic acid and clopidogrel has surely contributed to the severity of the hemorrhage. Recent experimental and clinical evidence suggests a possible antiplatelet effect of the statins.

[Gastrointestinal opportunistic infections and human immunodeficiency virus (HIV). Case report]. / Infezioni opprtuniste gastrointestinali e HIV. Caso clinico.

There have been millions of people found to have AIDS. Death rates from AIDS have declined 15% to 20% in the past 5 years. However, nearly 75000 people will die with AIDS in this year. Patients with AIDS are also at risk for developing both Aids-defining cancers, such as Kaposi's sarcoma and non-Hodgkin lymphoma, and non-Aids-defining cancers and opportunistic infections. In patients with advanced Aids, the Cytomegalovirus is a frequent cause of chorioretinitis, pneumonitis, chronic perineal ulcerations and oesophagitis. It has been involved in endocrine, bone marrow, central nervous system and kidney abnormalities. CMV infection of the small bowel accounts for only 4.3% of all cytomegalovirus infection of the GI tract (large bowel 47%, duodenum 21,7%, stomach 17,4%); isolated cases of small bowel perforation due to CMV have been reported in AIDS patients, and all but one patient died. The Authors report a rare case of an HIV-positive young man with gastroenteric Cytomegalovirus infection responsible for generalized peritonitis from multiple perforations.

mRNA surveillance mitigates genetic dominance in Caenorhabditis elegans.

Nonsense mutant mRNAs are unstable in all eucaryotes tested, a phenomenon termed nonsense-mediated mRNA decay (NMD) or mRNA surveillance. Functions of the seven smg genes are required for mRNA surveillance in Caenorhabditis elegans. In Smg(+) genetic backgrounds, nonsense-mutant mRNAs are unstable, while in Smg(-) backgrounds such mRNAs are stable. Previous work has demonstrated that the elevated level of nonsense-mutant mRNAs in Smg(-) animals can influence the phenotypic effects of heterozygous nonsense mutations. Certain nonsense alleles of a muscle myosin heavy chain gene are recessive in Smg(+) backgrounds but strongly dominant in Smg(-) backgrounds. Such alleles probably express disruptive myosin polypeptide fragments whose abundance is elevated in smg mutants due to elevation of mRNA levels. We report here that mutations in a variety of C. elegans genes are strongly dominant in Smg(-), but recessive or only weakly dominant in Smg(+) backgrounds. We isolated 32 dominant visible mutations in a Smg(-) genetic background and tested whether their dominance requires a functional NMD system. The dominance of 21 of these mutations is influenced by NMD. We demonstrate, furthermore, that in the case of myosin, the dominant-negative effects of nonsense alleles are likely to be due to expression of N-terminal nonsense-fragment polypeptides, not to mistranslation of the nonsense codons. mRNA surveillance, therefore, may mitigate potentially deleterious effects of many heterozygous germline and somatic nonsense or frame-shift mutations. We also provide evidence that smg-6, a gene previously identified as being required for NMD, performs essential function(s) in addition to its role in NMD.