Analysis of polyphosphate in mammalian cells and tissues: methods, functions and challenges.

Polyphosphates play a crucial role in various biological processes, such as blood coagulation, energy homeostasis, and cellular stress response. However, their isolation, detection, and quantification present significant challenges. These difficulties arise primarily from their solubility, low concentration in mammals, and structural similarity to other ubiquitous biopolymers. This review provides an overview of the current understanding of polyphosphates in mammals, including their proposed functions and tissue distribution. It also examines key isolation techniques, such as chromatography and precipitation, alongside detection methods, such as colorimetric assays and enzymatic digestion. The strengths and limitations of these methods are discussed, as well as the challenges in preserving polyphosphate integrity. Recent advancements in isolation and detection are also highlighted, offering a comprehensive perspective essential for advancing polyphosphate research.

Tomografía computarizada en el posoperatorio de cirugía abdominal mayor / Computed tomography scan after major abdominal surgery

RESUMEN Antecedentes: las cirugías abdominales mayores pueden presentar complicaciones posoperatorias graves cuya detección temprana resulta importante para su tratamiento. Objetivo: determinar la utilidad del uso de la tomografía computarizada (TC) para el diagnóstico temprano de las complicaciones de cirugía abdominal mayor. Materiales y métodos: estudio retrospectivo observacional descriptivo, mediante revisión de historias clínicas de pacientes operados de cirugía abdominal mayor en un Hospital Privado. Se agruparon los pacientes según presentaban o no síntomas sospechosos de complicación posoperatoria. Los primeros se clasificaron en 3 grupos: sin TC, con TC con hallazgos positivos y con TC sin hallazgos patológicos. Resultados: se analizaron 154 pacientes, con un promedio de edad de 61,3 ± 12,5 años; 83 (54%) fueron varones. Sobre 48 pacientes (31%) con síntomas sospechosos de complicaciones, fueron reoperados 6 sin TC, pero con síntomas muy evidentes, 7 con signos tomográficos positivos y 14/41 del grupo con TC negativa. Todos tuvieron hallazgos que justificaron la intervención. Hubo 27 casos (17,5%) con complicaciones IIIb según Clavien-Dindo y 3 pacientes (2%) fallecieron. Conclusión: la tomografía computarizada tuvo valor para confirmar una complicación, pero no para descartarla. Los parámetros clínicos cobran especial importancia en los pacientes sintomáticos sin hallazgos patológicos en la TC posoperatoria.

ABSTRACT Background: Major abdominal surgeries may present serious postoperative complications that require early diagnosis. Objective: The aim of this study was to determine the usefulness of computed tomography (CT) for the early diagnosis of major abdominal surgery complications. Material and methods: We conducted a retrospective, observational and descriptive study using data obtained from the medical records of patients undergoing major abdominal surgery in a private hospital. Patients were divided into two groups according to the presence or absence of symptoms suggesting a postoperative complication. Patients with symptoms were classified into 3 groups: without CT, with CT with positive findings and with CT without abnormal findings. Results: A total of 154 patients were analyzed; mean age was 61.3 ± 12.5 years and 83 (54%) were male. Of 48 patients (31%) with symptoms suggestive of complications, 6 had very evident symptoms and were re-operated without CT, 7 had positive findings on CT and CT was negative in 14/41. All the patients had findings that supported the decision to re-operate. There were 27 cases (17.5%) with grade 3b complications of the Clavien-Dindo classification and 3 patients (2%) died. Conclusion: Computed tomography was useful to confirm a complication, but not to rule it out. Clinical parameters remain of utmost importance in patients with symptoms and absence of abnormal findings in post-operative CT.

Prospective clinical trial of masitinib mesylate treatment for advanced stage III and IV canine malignant melanoma.

OBJECTIVE: To investigate efficacy of masitinib mesylate for the treatment of advanced malignant melanoma in dogs. MATERIALS AND METHODS: Prospective clinical trial on 17 dogs with stage III and IV malignant melanoma (two digital, one anal and 14 oral mucosal). Only dogs with advanced gross disease for which the owner declined conventional treatment or dogs with progressive tumour despite conventional treatment were included. RESULTS: There was a partial response in two dogs, stable disease in seven and tumour progression in eight dogs. Median survival time for all 17 dogs was 119 days (range 21-255). Masitinib was generally well-tolerated but grade 2 anaemia, grade 1 neutropenia, grade 1 diarrhoea and grade 2 anorexia were observed in one dog each. CLINICAL SIGNIFICANCE: There was only mild effectiveness in end-stage disease, indicating that masitinib mesylate is not an appropriate sole-agent option for treatment of advanced malignant melanoma in dogs.

Idiopathic sterile pyogranuloma in three domestic cats.

Pyogranulomatous inflammation has been extensively described in cats, in particular in cases of feline infectious peritonitis and also associated with Mycobacteria, Actinomyces, Nocardia, Rhodococcus and fungal infections. Idiopathic sterile pyogranulomatous dermatitis has also been described. In this case series we describe the clinical presentation, histopathology and outcome of three cases of feline idiopathic sterile steroid-responsive pyogranuloma with different presentation and different locations of the lesion, but with the common feature of having a mass with no superficial skin involvement.

Prospective nonrandomized study to evaluate cone beam computed tomography for technical assessment of standard and complex endovascular aortic repair.

OBJECTIVE: The objective of this study was to analyze the utility of cone beam computed tomography (CBCT) for technical assessment of standard and complex endovascular aneurysm repair (EVAR). METHODS: Data of consecutive patients who underwent standard or complex EVAR in 2016 and 2017 at our institution were entered into a prospective database and analyzed retrospectively. There were 154 patients (126 male; mean age, 74 ± 8 years) enrolled in a prospective study between 2016 and 2017. A total of 170 aortic procedures were investigated, including 85 fenestrated-branched EVARs (F-BEVARs), 42 abdominal and thoracic EVARs, 32 EVARs with iliac branch devices, and 11 aorta-related interventions. Technical assessment was done using CBCT with and without contrast enhancement, digital subtraction angiography (DSA), and computed tomography angiography (CTA). Patients with stage 3B or stage 4 chronic kidney disease had CBCT without contrast enhancement. Radiation exposure (mean dose-area product), effective dose (ED), and amount of iodine contrast agent were analyzed. End points were presence of any endoleak, positive findings warranting possible intervention (stent kink or compression, type I or type III endoleak, dissection, thrombus), and need for secondary intervention. RESULTS: Radiation exposure and amount of iodine contrast agent were significantly higher (P < .05) for F-BEVAR compared with other aortic procedures (174±101 Gy∙cm2 vs 1135±113 Gy∙cm2 and 144±60 mL vs 122±49 mL). ED averaged 74±36 mSv for the aortic procedure, 18 ± 18 mSv for fluoroscopy, 7 ± 7 mSv for DSA acquisition, 15±7 mSv for CBCT, and 34±17 mSv for CTA imaging (P < .001). Endoleak detection was significantly higher (P < .001) with CBCT (53%) compared with DSA (14%) and CTA (46%). CBCT identified 52 positive findings in 43 patients (28%), higher for F-BEVAR compared with other aortic procedures (35% vs 16%; P = .01). Positive findings included stent compression or kink in 29 patients (17%), type I or type III endoleak in 16 patients (10%), and arterial dissection or thrombus in 7 patients (5%). Of these, 28 patients (18%) had positive findings that prompted an intraoperative (17%) or delayed intervention (1%). Another 15 patients (10%) with minor positive findings were observed with no clinical consequence. DSA alone would not have detected positive findings in 34 of 43 patients (79%), including 21 patients (49%) who needed secondary interventions. CTA diagnosed two (1%) additional endoleaks requiring intervention (one type IC, one type IIIC) that were not diagnosed by CBCT. Replacing DSA and CTA by CBCT would have resulted in 53% ± 13% reduction in amount of iodine contrast agent and 55% ± 12% reduction in ED (P < .05). CONCLUSIONS: CBCT reliably detected positive findings prompting immediate revisions in nearly one of five patients, with the highest rates among F-BEVAR patients. Detection of any endoleak was higher with CBCT compared with DSA or CTA, but most endoleaks were observed. DSA alone failed to detect positive findings warranting revisions.

Comparison of Perioperative Outcomes of Patients with Iliac Aneurysms Treated by Open Surgery or Endovascular Repair with Iliac Branch Endoprosthesis.

BACKGROUND: Treatment of common and internal iliac aneurysms is usually done by open surgery. A novel iliac branch endoprosthesis (IBE) is commercially available with encouraging initial results. Our objective is to compare perioperative outcomes of patients with iliac aneurysms treated by open surgery (OS) versus endovascular repair with IBE. METHODS: The study was a retrospective, single-center review of patients who were treated for aortoiliac or isolated common and/or internal iliac artery aneurysms from 2014 to 2017. Patients with connective tissue disorders, infected grafts, or thoracoabdominal aneurysms were excluded. Primary outcomes were perioperative mortality, length of hospital (LOS) and intensive care unit (ICU) stay, estimated blood loss, need for red blood cell transfusion (RBC), and perioperative reinterventions. RESULTS: Sixty-seven patients (96% male) were treated with OS (n = 25, mean age 68 ± 8 years) or IBE (n = 42, mean age 73 ± 8 years; P = 0.02) with 1 symptomatic patient in each group. Perioperative mortality occurred in 1 patient in the OS group (4%), with no mortality in the IBE group (P = 0.37) Total LOS and ICU stay was higher for OS compared to IBE (total stay 7.5 ± 3.4 vs. 1.7 ± 1.4 days for IBE, P < 0.0001 and ICU LOS 3.3 ± 2.1 vs. 0.1 ± 0.4 days, P < 0.0001). Estimated blood loss was higher for patients undergoing OS (4,732 ± 2,540 mL) compared to patients treated with IBE (263 ± 451 mL, P < 0.0001), resulting in higher RBC transfusion requirements (1.5 ± 2.4 vs. 0.2 ± 0.8 units, P = 0.001). Five patients in the OS group had early procedure-related reinterventions, while 2 patients in the IBE group required reintervention for access site complications (20% vs. 4.7%, P = 0.09). CONCLUSIONS: Endovascular repair of iliac aneurysms with IBE is feasible and is associated with lower blood loss, LOS and ICU stay, and had lower RBC transfusion requirements. Cost analysis and long-term follow-up will be needed to define the value of this modality for iliac artery aneurysm repair.

Outcomes of upper extremity access during fenestrated-branched endovascular aortic repair.

OBJECTIVE: Upper extremity (UE) access is frequently used during fenestrated-branched endovascular aortic repair (F-BEVAR) to facilitate catheterization of downgoing vessels. Limitations include risk of cerebral embolization and of UE arterial or peripheral nerve injury. The aim of this study was to assess outcomes of F-BEVAR using UE access. METHODS: We reviewed the clinical data of 334 consecutive patients (74% males; mean age 75 ± 8 years) treated by F-BEVAR for thoracoabdominal aortic aneurysms or pararenal aortic aneurysms between 2007 and 2016. Patients who underwent F-BEVAR with an UE approach for catheterization of the renal and/or mesenteric arteries were included in the study. End points were technical success, mortality, and a composite of access-related complications including cerebral embolization (stroke/transient ischemic attack), peripheral nerve injury, and axillary-brachial arterial complications requiring intervention. RESULTS: There were 243 patients (73%) treated by F-BEVAR with UE access, including 147 patients (60%) with thoracoabdominal aortic aneurysms and 96 patients (40%) with pararenal aortic aneurysms. A total of 878 renal-mesenteric arteries were incorporated by fenestrations or branches with a mean of 3.6 ± 0.8 vessels per patient. All patients had surgical exposure of the brachial artery. The left side was selected in 228 (94%) and the right side in 15 (6%). The technical success of target vessel incorporation was achieved in 99% of patients (870 of 878). Arterial closure was performed using primary repair in 213 patients (88%) or bovine patch angioplasty in 29 (12%). Patch closure was required in 13% of patients (21 of 159) treated by 10- to 12F sheaths and 8% (7 of 83) of those who had 7- to 8F sheaths (P = .19). There were six deaths (2.5%) at 30 days or within the hospital stay, none owing to access-related complications. Major access-related complication occurred in eight patients (3%), with no difference between the 10- to 12F (6 of 159 [4%]) or 7- to 8F sheaths (2 of 83 [2%]; P = .45). Two patients (1%) had transient median nerve neuropraxia, which resolved within 1 year. One patient (0.5%) required surgical evacuation of an access site hematoma. There were no UE arterial pseudoaneurysms, occlusions, or distal embolizations. Five patients (2%) had strokes (three minor, two major), occurring more frequently with right side (2 of 15 [13%]) as compared with left-sided access (3 of 228 [1%]; P = .03). After a mean follow-up of 38 ± 15 months, there were no other access-related complications or reinterventions. CONCLUSIONS: UE arterial access with surgical exposure was associated with a low rate of complications in patients treated with F-BEVAR. Closure with patch angioplasty is frequently needed, but there were no arterial occlusions, pseudoaneurysms, or distal embolizations requiring secondary procedures.

Cross-sectional associations between cutaneous viral infections and regulatory T lymphocytes in circulation.

BACKGROUND: Cutaneous viral infections and immune suppression are risk factors for some forms of nonmelanoma skin cancer; however, their interrelationship is poorly understood. OBJECTIVES: To examine cross-sectional associations between cutaneous viral infections and circulating forkhead-box P3 (FOXP3)-expressing T-regulatory (Treg) cells, suppressive cells that dampen effective antitumour immunity. MATERIALS AND METHODS: Blood, eyebrow hair (EBH) and skin swab (SSW) samples were collected from 352 patients 60 years and older undergoing skin screening, without prevalent skin cancer, while participating in an ongoing prospective cohort study of cutaneous viral infections and skin cancer. DNA corresponding to 98 cutaneous human papillomavirus (HPV) types and five human polyomaviruses (HPyV) was assessed in EBH and SSW. Distinct classes of circulating Treg-cell subpopulations were defined by flow cytometry including cutaneous lymphocyte antigen (CLA) and CCR4high Treg cells, both previously associated with cutaneous diseases. Age- and sex-adjusted associations between circulating T-cell populations and infection were estimated using logistic regression. RESULTS: Total Treg-cell proportion in peripheral blood was not associated with ß HPV or HPyV infection. However, the proportion of circulating CLA+ Treg cells was inversely associated with γ HPV EBH infection [odds ratio (OR) 0·54, 95% confidence interval (CI) 0·35-0·84]. Interestingly, circulating Treg cells expressing markers indicative of antigen activation (CD27- CD45RA- FOXP3+ CD4+ ) were also inversely associated with γ HPV infection in SSW (OR 0·55, 95% CI 0·30-0·99) and EBH (OR 0·56, 95% CI 0·36-0·86). CONCLUSIONS: Inverse associations between circulating Treg cells and γ HPV infection suggest that localized viral infection may promote immunosuppressive cell migration into skin.

Outcomes of an iliac branch endoprosthesis using an "up-and-over" technique for endovascular repair of failed bifurcated grafts.

OBJECTIVE: Type IB endoleak after endovascular aneurysm repair may be treated by an iliac branch endoprosthesis (IBE) through brachial access for internal iliac artery (IIA) stenting. The aim of this study was to evaluate outcomes of the IBE using an "up-and-over" transfemoral technique in patients with prior aortic repair compared with the standard technique in patients with de novo iliac aneurysms. METHODS: We reviewed the clinical data of patients treated for aortoiliac aneurysms using Gore IBE (W. L. Gore & Associates, Flagstaff, Ariz) between 2014 and 2017. The up-and-over technique was indicated in patients with type IB endoleak or common iliac aneurysms after prior aortic repair with bifurcated endografts or surgical grafts. End points were technical success, mortality, major adverse events, IIA patency, freedom from IIA branch instability (composite end point of any IIA branch-related complication leading to aneurysm rupture, death, occlusion, component separation, or reintervention to maintain branch patency or to treat a branch-related separation or endoleak), and freedom from secondary interventions or new-onset buttock claudication. RESULTS: There were 53 patients (51 male; 74 ± 8 years old) treated by 62 IBEs (9 bilateral). Standard technique was used in 36 patients (43 IBEs) and up-and-over technique in 17 (19 IBEs). Three patients had contralateral IIA embolization. Total procedure time, contrast material volume, and radiation dose averaged 168 ± 98 minutes, 140 ± 50 mL, and 1096 ± 1009 mGy, with no difference between techniques. Technical success was achieved in 98% of patients. Eleven patients had extension of IIA bridging stent into the posterior branch (eight standard, three up-and-over). Four patients (8%) had major adverse events due to estimated blood loss >1000 mL in all patients. There was no 30-day mortality after a median follow-up of 7 months (interquartile range, 3-12 months). There were two IIA stent occlusions (all standard), three iliac-related type I endoleaks (one standard, two up-and-over), and four secondary interventions (three standard, one up-and-over). At 1 year, patients treated by standard or up-and-over technique had similar primary patency (94% ± 4% vs 100%; P = .38) and secondary patency (97% ± 3% vs 100%; P = .54) and freedom from IIA branch instability (90% ± 6% vs 93% ± 7%; P = .48), secondary intervention (84% ± 8% vs 90% ± 9%; P = .63), and new-onset buttock claudication (90% ± 6% vs 100%; P = .35). CONCLUSIONS: Endovascular repair using IBE was associated with high technical success, no mortality, and low rate of complications using either the standard technique for de novo aneurysms or an up-and-over technique for patients with failed bifurcated endografts or grafts. The up-and-over technique should be considered a suitable alternative to brachial access in patients who require distal extension using IBEs.

Evolution from physician-modified to company-manufactured fenestrated-branched endografts to treat pararenal and thoracoabdominal aortic aneurysms.

OBJECTIVE: The purpose of this study was to review treatment trends and outcomes of patients who underwent fenestrated-branched endovascular aneurysm repair (F-BEVAR) of pararenal aneurysms (PRAs) or thoracoabdominal aortic aneurysms (TAAAs) using physician-modified endografts (PMEGs) or company-manufactured devices (CMDs). METHODS: We reviewed the clinical data of 316 consecutive patients (242 male patients; mean age, 75 ± 8 years) who underwent F-BEVAR between 2007 and 2016. F-BEVAR was performed under two prospective investigational device exemption protocols since 2013. End points were mortality, major adverse events (MAEs), patient survival, reintervention, branch instability, aneurysm-related mortality, renal function deterioration, and target vessel patency. RESULTS: There were 145 patients (46%) treated by PMEGs (84 PRAs, 26 extent IV and 35 extent I-III TAAAs) and 171 patients (54%) who had CMDs (88 PRAs, 42 extent IV and 41 extent I-III TAAAs). Choice of endograft evolved from PMEGs in 131 patients (83%) treated in the first half of experience to CMDs in 144 patients (91%) treated in the second half of experience (P < .001). Patients treated by PMEGs had significantly (P < .05) larger aneurysms, more chronic pulmonary and kidney disease, and higher comorbidity severity scores. A total of 1081 renal-mesenteric arteries were targeted in both groups. Technical success was lower for PMEGs (98% vs 99.5%; P = .02). Thirty-day mortality was 5.5% for PMEGs (PRAs, 1.2%; extent IV 3.8% and extent I-III, 17.1%) and 0% for CMDs (P = .0018). Patients treated by PMEGs had significantly more (P < .001) MAEs (48% vs 23%) and longer hospital stay (9 ± 10 days vs 6 ± 6 days; P = .001). Mean follow-up was significantly longer for patients treated by PMEGs (38 ± 26 months vs 14 ± 12 months; P < .001). At 3 years, patient survival (68% ± 4% vs 67% ± 8%; P = .11), freedom from reintervention (68% ± 4% vs 68% ± 8%; P = .17), primary (94% ± 2% vs 92% ± 2%; P = .64) and secondary target vessel patency (98% ± 1% vs 98% ± 1%; P = .89), and freedom from renal function deterioration (75% ± 4% vs 65% ± 6%; P = .24) were similar for patients treated by PMEGs or CMDs, respectively. CONCLUSIONS: Choice of F-BEVAR evolved from PMEGs to almost exclusively CMDs under physician-sponsored investigational device exemption protocols. PMEG patients had more comorbidities and larger aneurysms. CMDs were performed with higher technical success, no mortality, and fewer MAEs.

Impact of onlay fusion and cone beam computed tomography on radiation exposure and technical assessment of fenestrated-branched endovascular aortic repair.

OBJECTIVE: The objective of this study was to analyze the impact of advanced imaging applications and cone beam computed tomography (CBCT) on radiation exposure of the patient and operator and detection of technical problems during fenestrated-branched endovascular aortic repair (F-BEVAR) for treatment of pararenal aneurysms and thoracoabdominal aortic aneurysms (TAAAs). METHODS: We reviewed the clinical data of 386 consecutives patients (289 male; mean age, 75 ± 8 years) treated by F-BEVAR for 196 pararenal aneurysms and 190 TAAAs (mean, 3.4 ± 0.9 targeted vessels/patient) between 2007 and 2017. Radiation exposure (cumulative air kerma) was analyzed in three fixed imaging systems used between 2007 and 2011 (system 1), 2012 and 2016 (system 2), and 2016 and 2017 (system 3). Onlay fusion and CBCT were available with systems 2 and 3, whereas digital zoom with fusion overlay was used with system 3. Operator effective dose was measured per month using a radiation dosimeter badge. Computed tomography angiography and CBCT were analyzed for findings requiring immediate revision or secondary interventions. End points were patient radiation exposure; operator effective dose; procedure technical success; and 30-day rates of mortality, major adverse events, and secondary interventions. RESULTS: F-BEVAR was performed using system 1 in 98 patients, system 2 in 198 patients, and system 3 in 90 patients. Use of onlay fusion/CBCT was 0% with system 1, 42% with system 2, and 98% with system 3. Procedures performed with onlay fusion/CBCT had significantly (P < .05) higher technical success (99.4% vs 98.8%) and lower contrast material volume (155 ± 58 mL vs 172 ± 80 mL), fluoroscopy time (83 ± 34 minutes vs 94 ± 49 minutes), and cumulative air kerma (2561 ± 1920 mGy vs 3767 ± 2307 mGy). Despite higher case volume and increasing complexity during the experience, operator effective dose decreased to 9 ± 4 × 10-2 mSv/case with system 3 compared with 26 ± 3 × 10-2 mSv/case with system 1 and 20 ± 2 × 10-2 mSv/case with system 2 (P = .001). Among 219 patients who had no CBCT, 18 (8%) had computed tomography angiography findings that prompted secondary interventions before dismissal. Conversely, among 167 patients who had CBCT, 14 patients (8%) had intraoperative CBCT findings requiring immediate revision, with no additional secondary interventions. Patients treated with onlay fusion/CBCT had significantly (P < .05) lower mortality (4% vs 1%), major adverse events (43% vs 19%), and secondary interventions (10% vs 4%) at 30 days. CONCLUSIONS: Radiation exposure and operator effective dose significantly decreased with evolution of F-BEVAR experience and use of advanced imaging applications such as onlay fusion and CBCT. CBCT allowed immediate assessment and identified intraoperative technical problems, leading to immediate revision and avoiding early secondary interventions.

Evaluation of Histological, Immunohistochemical, Clinical and Genetic Prognostic Factors Associated with the Response of Canine Mast Cell Tumours to Glucocorticotherapy.

Mast cell tumours (MCTs) are one of the most frequent neoplasms in dogs. Glucocorticoids (GCs) are widely used in the management of this disease, although no guidelines for their use have been established. The aim of this study was to evaluate the correlation of MCT prognostic factors with measurable response to GCs. This retrospective study included 60 dogs treated with prednisone or prednisolone prior to surgical biopsy of MCT. Incisional or excisional biopsy was performed 7-14 days after initiation of GC therapy. Histopathology, immunohistochemical labelling for Ki67 and KITr, and polymerase chain reaction for the c-KIT gene were performed. Partial response occurred in 63.3% of cases (38/60), while 36.7% (22/60) did not respond. A response to GCs was correlated with lower stage of the disease, low histological grade, lower pattern of KITr expression and Ki67 score. Response to GCs was positively correlated with well-established favourable prognostic factors.

Severe infolding of fenestrated-branched endovascular stent graft.

Infolding of a fenestrated-branched stent graft is an infrequent complication due to excessive oversizing. We report the case of an 89-year-old man who underwent a four-vessel fenestrated-branched endovascular aortic repair for a pararenal aortic aneurysm. Computed tomography angiography revealed severe infolding across the mesenteric-renal vessels. The patient was treated by angioplasty and placement of Palmaz stent. Cone-beam computed tomography confirmed patent visceral vessels with resolution of the infolding. This case illustrates an uncommon complication that can be prevented by modifications in the stent design and by immediate assessment using intraoperative cone-beam computed tomography.

Safety profile of the 9-valent human papillomavirus vaccine: assessment in prior quadrivalent HPV vaccine recipients and in men 16 to 26 years of age.

A 9-valent HPV (9vHPV) vaccine has been developed to protect against HPV type 6/11/16/18/31/33/45/52/58-related infection and disease. Previous safety analyses from 7 clinical trials conducted in 9vHPV vaccine recipients 9-26 years of age, including comparisons of 9vHPV and quadrivalent HPV (qHPV) vaccines in girls and women 16-26 years of age, showed that the 9vHPV vaccine was generally well tolerated. Additional safety analyses were conducted to include the results of new clinical studies. The safety profile of the 9vHPV vaccine in prior qHPV vaccine recipients (n = 3756 from 1 randomized controlled trial and 2 open-label extension studies) and young men (n = 248 9vHPV and n = 248 qHPV vaccine recipients from 1 randomized controlled trial) was evaluated. Vaccine was administered as a 3-dose regimen (at Day 1 and Months 2 and 6), and adverse events (AEs) were monitored. The most common AEs were injection-site events (91.1% and 79.0% in prior qHPV vaccine recipients and young men, respectively), the majority of which were mild. Discontinuations due to an AE were rare (0.2% and 0.0% among prior qHPV vaccine recipients and young men, respectively). In young men, the AE profile of the 9vHPV vaccine was generally similar to that of the qHPV vaccine. Overall, the 9vHPV vaccine was generally well tolerated in prior qHPV vaccine recipients and in young men, with an AE profile generally consistent with that previously reported with the broader clinical program.

FOXC1: an emerging marker and therapeutic target for cancer.

The Forkhead box C1 (FOXC1) transcription factor is involved in normal embryonic development and regulates the development and function of many organs. Most recently, a large body of literature has shown that FOXC1 plays a critical role in tumor development and metastasis. Clinical studies have demonstrated that elevated FOXC1 expression is associated with poor prognosis in many cancer subtypes, such as basal-like breast cancer (BLBC). FOXC1 is highly and specifically expressed in BLBC as opposed to other breast cancer subtypes. Its functions in breast cancer have been extensively explored. This review will summarize current knowledge on the function and regulation of FOXC1 in tumor development and progression with a focus on BLBC, as well as the implications of these new findings in cancer diagnosis and treatment.

Expression of Fibroblast Activating Protein and Correlation with Histological Grade, Mitotic Index and Ki67 Expression in Canine Mast Cell Tumours.

Fibroblast activating protein (FAP) is a membrane serine protease expressed by activated fibroblasts, particularly tumour associated fibroblasts (TAFs). FAP expression has not been reported in canine mast cell tumours (MCTs). The objective of this study was to evaluate the expression of FAP in TAFs and its correlation with histological grade, mitotic index and Ki67 expression in canine MCTs. FAP expression was evaluated by immunohistochemistry (IHC) in 30 canine MCTs. Twenty-eight (90%) of the MCTs expressed FAP in the stroma, 16 cases showed low to intermediate FAP score and 14 cases had a high FAP score. FAP was correlated positively with both Patnaik (P = 0.007) and Kiupel (P = 0.008) grading systems, mitotic index (P = 0.0008) and Ki67 expression (P = 0.009). High stromal FAP expression could be a potential negative prognostic factor in canine MCTs.

Distribution and factors associated with salivary secretory leukocyte protease inhibitor concentrations.

OBJECTIVES: This cross-sectional study examined the distribution and correlates of salivary secretory leukocyte protease inhibitor (SLPI) concentrations within a multinational cohort of men. METHODS: Extracellular SLPI was measured in oral gargle cell supernatants of 378 men from three countries using an ELISA-based assay. Risk factor data were collected by a questionnaire. Factors associated with SLPI were assessed using linear and logistic regression for continuous and categorical SLPI, respectively. RESULTS: Among men aged 18-73 years, the median SLPI concentration was 492.0 ng ml-1 (range: 2.3-1919.9). In multivariable modeling, men in Brazil and younger men (18-30 years) were more likely to have higher levels of SLPI [adjusted odds ratio (aOR) 3.84; 95% confidence interval (CI): 1.94-7.59, and aOR 3.84; 95% CI: 1.98-7.43, respectively]. Men with a self-reported sexually transmitted diseases diagnosis in the past 6 months were more likely to have higher SLPI levels (aOR 2.98; 95% CI: 1.1-7.83) and men reporting bleeding/swollen gums were less likely to have higher SLPI (aOR 0.34; 95% CI: 0.15-0.79). Similar results were observed for linear regression models. CONCLUSIONS: Secretory leukocyte protease inhibitor concentrations varied significantly by country and decreased with increasing age. The interaction between SLPI, modifiable factors, and oral infections that influence cancer risk warrants further investigation.

FOXC1 is involved in ERα silencing by counteracting GATA3 binding and is implicated in endocrine resistance.

Estrogen receptor-α (ERα) mediates the essential biological function of estrogen in breast development and tumorigenesis. Multiple mechanisms, including pioneer factors, coregulators and epigenetic modifications have been identified as regulators of ERα signaling in breast cancer. However, previous studies of ERα regulation have focused on luminal and HER2-positive subtypes rather than basal-like breast cancer (BLBC), in which ERα is underexpressed. In addition, mechanisms that account for the decrease or loss of ER expression in recurrent tumors after endocrine therapy remain elusive. Here, we demonstrate a novel FOXC1-driven mechanism that suppresses ERα expression in breast cancer. We find that FOXC1 competes with GATA-binding protein 3 (GATA3) for the same binding regions in the cis-regulatory elements upstream of the ERα gene and thereby downregulates ERα expression and consequently its transcriptional activity. The forkhead domain of FOXC1 is essential for the competition with GATA3 for DNA binding. Counteracting the action of GATA3 at the ERα promoter region, overexpression of FOXC1 hinders recruitment of RNA polymerase II and increases histone H3K9 trimethylation at ERα promoters. Importantly, ectopic FOXC1 expression in luminal breast cancer cells reduces sensitivity to estrogen and tamoxifen. Furthermore, in breast cancer patients with ER-positive primary tumors who received adjuvant tamoxifen treatment, FOXC1 expression is associated with decreased or undetectable ER expression in recurrent tumors. Our findings highlight a clinically relevant mechanism that contributes to the low or absent ERα expression in BLBC. This study suggests a new paradigm to study ERα regulation during breast cancer progression and indicates a role of FOXC1 in the modulation of cellular response to endocrine treatment.

Metastatic anal sac carcinoma with hypercalcaemia and associated hypertrophic osteopathy in a dog.

A seven-year-old male neutered Irish setter was treated for a metastatic anal sac adenocarcinoma (ASAC) and hypercalcaemia by complete surgical excision of the primary tumour and partial excision of the sublumbar lymph nodes. Further enlargement of the sublumbar lymph nodes was linked to recurrent hypercalcaemia 3 months after surgical treatment. Medical treatment with Toceranib and Clodronate showed modest results in the treatment of the tumour and the hypercalcaemia. Radiotherapy of the sublumbar lymph nodes and later concurrent carboplatin chemotherapy resulted in partial tumour remission with marked reduction in size of the lymph nodes and normalization of the calcaemia. Unfortunately, concurrently with subsequent relapse of the hypercalaemia, the dog developed hypertrophic osteopathy (HO) and lumbar spinal metastasis and the dog was euthanized. To the authors' knowledge, this is the second case of metastatic apocrine gland carcinoma of the anal sac associated with HO and the first case that describe the development of HO late in the stage of the disease.