First-in-human study of CPL207280, a novel G-protein-coupled receptor 40/free fatty acid receptor 1 agonist, in healthy volunteers after single and multiple administration.

AIM: To assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of CPL207280, a new G-protein-coupled receptor 40 agonist developed to treat type 2 diabetes (T2D). METHODS: The phase 1 study in healthy volunteers (White, age 18-55 years, body mass index 18.5-29.9 kg/m2 ) was performed after single (24 subjects, 5-480 mg) and multiple (32 subjects, 60-480 mg) once-daily administration of CPL207280.  The effect of food intake and interaction with metformin were evaluated in additional cohort (12 subjects, 120 mg). The primary objective was the safety and tolerability of CPL207280. Secondary objectives included PK and pharmacodynamic (PD) characteristics (glucose, insulin, C-peptide, proinsulin, glucagon levels) observed during the 14-day treatment period. RESULTS: No deaths or serious adverse events (AEs) were reported. All reported AEs were classified as unrelated to the study product. No clinically significant differences in safety parameters were observed between cohorts and no food or metformin effect on safety parameters was identified. The ascending dose of CPL207280 caused an increase in the PK parameters maximum observed plasma concentration (Cmax ) or area under the plasma concentration-time curve up to 24 h. However, dose-normalized Cmax decreased with ascending dose. There was no relationship between the CPL207280 dose or prandial state and terminal elimination half-life and terminal elimination rate constant. No clear relationship between CPL207280 dose and PD area under the effect curve values was observed. CONCLUSIONS: CPL207280 was found to be safe and well tolerated by healthy volunteers (with a low risk of hepatotoxicity) for up to 14 days of administration. The PK profile of CPL207280 supports single-daily administration and justifies further development of this therapy for patients with T2D.

Detection of a second primary cancer in a 18F-fluorocholine PET/CT - multicentre retrospective analysis on a group of 1345 prostate cancer patients.

BACKGROUND: Aim of this study was to evaluate the rate of incidental detection of second primary cancer (SPC) at 18F-fluorocholine ([18F]FCH) positron emission tomography/computed tomography (PET/CT) performed in prostate cancer patients. MATERIAL AND METHODS: A retrospective analysis was performed on a group of 1345 prostate cancer patients, who underwent [18F]FCH PET/CT study because of suspicion of recurrence (n = 937) or for initial staging (n = 408). Images were acquired after intravenous injection [18F]FCH with a mean activity of 200 ± 75 MBq (5.4 ± 2 mCi), from the top of the head to the half of the thigh. The confirmation of second primary cancer was obtained from the cancer registry. RESULTS: Based on the [18F]FCH PET/CT scans, a second primary cancer was suspected in 89 patients (6.6%). Of these, a malignancy was histologically confirmed in 26 patients (29% of all suspected findings and 1.9% of the complete cohort). Lung cancer (including adenocarcinoma, neuroendocrine cancer) was diagnosed in 13 patients (50%) and hematologic neoplasm (including chronic lymphocytic leukemia, Hodgkin lymphoma, follicular lymphoma, and multiple myeloma) in 5 patients (19%). 18F-fluorocholine PET/CT also revealed esophageal cancer, mesothelioma, testicular, renal, bladder, and colorectal cancer inindividual patients, non-keratinizing squamous cell carcinoma (SCC) of the skin as well as head and neck SCC with unknown primary. CONCLUSION: We conclude that incidental detection of a second primary cancer in prostate cancer patients using [18F]FCH PET/CT is not very common and that lung cancer and hematologic malignancies are most frequently detected.

Loss of epidermal MCPIP1 is associated with aggressive squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma (SCC) of the skin is a common form of nonmelanoma skin cancer. Monocyte chemotactic protein 1-induced protein 1 (MCPIP1), also called Regnase-1, is an RNase with anti-inflammatory properties. In normal human skin, its expression is predominantly restricted to the suprabasal epidermis. The main aim of this study was to investigate whether MCPIP1 is involved in the pathogenesis of SCC. METHODS: We analyzed the distribution of MCPIP1 in skin biopsies of patients with actinic keratoses (AKs) and SCCs. To explore the mechanisms by which MCPIP1 may modulate tumorigenesis in vivo, we established a mouse model of chemically induced carcinogenesis. RESULTS: Skin expression of MCPIP1 changed during the transformation of precancerous lesions into cutaneous SCC. MCPIP1 immunoreactivity was high in the thickened area of the AK epidermis but was predominantly restricted to keratin pearls in fully developed SCC lesions. Accelerated development of chemically induced skin tumors was observed in mice with loss of epidermal MCPIP1 (Mcpip1eKO). Papillomas that developed in Mcpip1eKO mouse skin were larger and characterized by elevated expression of markers typical of keratinocyte proliferation and tumor angiogenesis. This phenotype was correlated with enhanced expression of IL-6, IL-33 and transforming growth factor-beta (TGF-ß). Moreover, our results demonstrated that in keratinocytes, the RNase MCPIP1 is essential for the negative regulation of genes encoding SCC antigens and matrix metallopeptidase 9. CONCLUSIONS: Overall, our results provide a mechanistic understanding of how MCPIP1 contributes to the development of epidermoid carcinoma.

Release of adenosine-induced immunosuppression: Comprehensive characterization of dual A2A/A2B receptor antagonist.

Immunosuppression is one of the main mechanisms facilitating tumor expansion. It may be driven by immune checkpoint protein expression, anti-inflammatory cytokine secretion or enhanced metabolic enzyme production, leading to the subsequent build-up of metabolites such as adenosine. Under physiological conditions, adenosine prevents the development of tissue damage resulting from a prolonged immune response; the same mechanism might be employed by tumor tissue to promote immunosuppression. Immune cells expressing A2A and A2B adenosine receptors present in an adenosine-rich environment have suppressed effector functions, such as cytotoxicity, proinflammatory cytokine release, antigen presentation and others, making them inert to cancer cells. This study was designed to investigate the dual antagonist potential of SEL330-639 to abolish adenosine-driven immunosuppression. SEL330-639 has slow dissociation kinetics. It inhibits cAMP production in human CD4+ cells, CD8+ cells and moDCs, which leads to diminished CREB phosphorylation and restoration of antitumor cytokine production (IL-2, TNFα, IL-12) in multiple primary human immune cells. The aforementioned results were additionally validated by gene expression analysis and functional assays in which NK cell line cytotoxicity was recovered by SEL330-639. Adenosine-driven immunosuppression is believed to preclude the effectiveness of immune checkpoint inhibitor therapies. Hence, there is an urgent need to develop new immuno-oncological strategies. Here, we comprehensively characterize SEL330-639, a novel dual A2A/A2B receptor antagonist effective in both lymphoid and myeloid cell populations with nanomolar potency. Due to its tight binding to the A2A and A2B receptors, this binding is sustained even at high adenosine concentrations mimicking the upper limit of the range of adenosine levels observed in the tumor microenvironment.

Evaluation of tramadol human pharmacokinetics and safety after co-administration of magnesium ions in randomized, single- and multiple-dose studies.

BACKGROUND: Magnesium ions (Mg2+) increase and prolong opioid analgesia in chronic and acute pain. The nature of this synergistic analgesic interaction has not yet been explained. Our aim was to investigate whether Mg2+ alter tramadol pharmacokinetics. Our secondary goal was to assess the safety of the combination. METHODS: Tramadol was administered to healthy Caucasian subjects with and without Mg2+ as (1) single 100-mg and (2) multiple 50-mg oral doses. Mg2+ was administered orally at doses of 150 mg and 75 mg per tramadol dosing in a single- and multiple-dose study, respectively. Both studies were randomized, open label, laboratory-blinded, two-period, two-treatment, crossover trials. The plasma concentrations of tramadol and its active metabolite, O-desmethyltramadol, were measured. RESULTS: A total of 25 and 26 subjects completed the single- and multiple-dose study, respectively. Both primary and secondary pharmacokinetic parameters were similar. The 90% confidence intervals for Cmax and AUC0-t geometric mean ratios for tramadol were 91.95-102.40% and 93.22-102.76%. The 90% confidence intervals for Cmax,ss and AUC0-τ geometric mean ratios for tramadol were 93.85-103.31% and 99.04-105.27%. The 90% confidence intervals for primary pharmacokinetic parameters were within the acceptance range. ANOVA did not show any statistically significant contribution of the formulation factor (p > 0.05) in either study. Adverse events and clinical safety were similar in the presence and absence of Mg2+. CONCLUSIONS: The absence of Mg2+ interaction with tramadol pharmacokinetics and safety suggests that this combination may be used in the clinical practice for the pharmacotherapy of pain.

[Chondrocytes application in regenerative medicine]. / Zastosowanie chondrocytów w medycynie regeneracyjnej.

Cartilage reconstruction is a crucial issue for tissue engineering because of high damage frequency in connection with low regenerative capacity. Microfractures and shaving are the oldest and most commonly used practices. The newest techniques are: Autologous Chondrocyte Implantation, Matrix Associated Chondrocytes Implantation and their derivatives. Dedifferentiation of chondrocytes due to low proliferation rate and phenotype loss makes isolation and in vitro culture of normal human chondrocytes very complex. Therefore, obtaining mesenchymal stem cells from various sources and differentiating them into chondrocytes is another interesting approach.

Morphological and immunohistological characteristics of follicular-compact thyroid carcinoma in dog.

The case of a 14-year-old mongrel dog with a thyroid tumor treated by thyreoidectomy is described. The resected tumor was subjected to a detailed morphological and immunohistochemical analysis utilizing antibodies directed against thyroglobulin, calcitonin, chromogranin A, cytokeratin 19, thyroid transcription factor-1, CD31, Ki-67 and minichromosome maintenance protein 3. Expression level of the above mentioned antigens allowed to characterize the resected tumor as thyroid follicular-compact carcinoma. Common application of immunohistochemistry may increase the diagnosis precision and efficacy of thyroid tumor treatment in dogs.

Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 7: A one-month, randomized, ambulatory, controlled clinical study in Poland.

This randomized, open-label, ambulatory, controlled clinical study investigated biomarkers associated with cardiovascular risk and biomarkers of exposure to 10 selected harmful and potentially harmful constituents (HPHC) in cigarette smoke in 316 male and female Polish smokers. Subjects were randomized to continue smoking conventional cigarettes (CC; N=79) or switch to smoking the Electrically Heated Cigarette Smoking System series-K cigarette (EHCSS-K6; N=237). Biomarker assessments were performed at several time points during the study at baseline and during the 1-month investigational period. The primary biomarkers were high-sensitivity C-reactive protein and white blood cell counts. No statistically significant differences in the two primary biomarkers were found between the study groups at the end of the study. End-of-study comparisons of secondary biomarkers between study groups indicated an increase in high-density lipoprotein cholesterol, and reductions in red blood cell count, hemoglobin, and hematocrit levels in the EHCSS-K6 group. All biomarkers of exposure to cigarette smoke HPHC were decreased in the EHCSS-K6 group, despite an increase in cigarette consumption, compared to the CC group. There were no apparent differences in any of the safety assessment parameters between the groups, and the overall incidence of study-related adverse events was low.

Cerebrovascular reactivity evaluated by transcranial doppler sonography in patients after aneurysmal subarachnoid haemorrhage treated with microsurgical clipping or endovascular coiling technique.

OBJECTIVE: To examine cerebrovascular reactivity in patients after subarachnoid haemorrhage (SAH) during long-term follow-up, using Acetazolamide test and transcranial Doppler (TCD) monitoring of blood flow velocities (BFVs), to compare of CO(2) reactivity between patients after SAH treated with three different methods: surgical (clipping), endovasculary (coiling) and conservative. METHODS: The study was performed in a group of 24 patients treated for SAH. Cerebrovascular reactivity (CVR) has been evaluated after intravenous administration of 1000 mg of Acetazolamide. Studied patients were divided into three groups: group I (n = 10) treated with clipping, group II (n = 8) treated with coiling and group III (n = 6)--patients with negative angiography treated conservatively. RESULTS: Results of this study have shown that: (1) BFVs were normal in cerebral arteries and did not differ between right and left head sides, (2) CVR was normal in all studied patients, (3) method of aneurysm treatment as well as its localization had no influence on BFV and CVR, and (4) occurrence of vasospasm in early days after SAH did not result in permanent disturbances of CO(2) arterial reactivity. CONCLUSION: BFV values in cerebral arteries were in normal range and did not differ on the left and right head sides. CVR was normal in all examinated patients. A method of the ruptured aneurysm treatment and its localization had no influence on CBFV and CRV. Vasospasm in early period after SAH did not provoke a persistent impairment of CO(2) reactivity.

Titanium and zirconium benzofuranoxides. Crystal structures and catalytic properties.

Reactions of Ti(OiPr)4 or Zr(OEt)4 with 4 equivalents of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (ddbfoH) in toluene gave neutral complexes that in the solid state are dimers of [Ti(micro-ddbfo)2(ddbfo)6] and [Zr(ddbfo)3(EtOH)(micro-EtO)]2 composition. The former could also be conveniently synthesized in a direct reaction of TiCl4 with ddbfoH. This air-stable aryloxo compound was found to initiate living ring-opening polymerization of lactides affording polyesters with narrow molecular weight distribution. It also catalyzed addition of terminal acetylenes to aryl aldehydes.

Early cerebral hemodynamic alternations in patients operated on the first, second and third day after aneurysmal subarachnoid hemorrhage.

Surgery timing after aneurysmal subarachnoid hemorrhage (SAH) may influence the risk of vasospasm after early surgical procedure and is correlated with SAH extensiveness. A group consisting of 127 patients with aneurysmal SAH was studied. The changes of mean flow velocity (MFV) were measured in middle cerebral artery (MCA) and in anterior cerebral artery (ACA) by transcranial Doppler sonography (TCD) in three groups of patients divided according to the surgery timing (on the first, second and third day after SAH). Changes of MFV values in MCA and in ACA were similar in all groups. MFV values in the group of patients operated on the third day were the lowest and the pathologic values lasted for the shortest time. In patients with massive SAH (Fisher IV group) and mild SAH (Fisher II group), the lowest MFV values were observed, if patients were operated within 24 hours after SAH. In patients without SAH (Fisher I group), the MFV values were the lowest, if they were operated on the third day after SAH. In patients with severe SAH (Fisher III group), the lowest risk of vasospasm was observed, if they were operated on the second day after SAH; however, the highest risk was found in patients operated on the first day after SAH. Our study suggests: (1) in patients with severe SAH operated on the second day, the lowest risk of vasospasm was observed, and the highest risk of vasospasm was observed if those were operated on the first day; (2) the highest risk of vasospasm was observed in patients operated within 24 hours with mild and massive SAH and in patients without SAH operated on the third day after SAH.

[Coexistence of occupational exposure to lead and sleep apnea syndrome as a cause of hypertension and arrhythmias. A case report]. / Wspólistnienie zawodowego narazenia na dzialanie olowiu oraz zespolu bezdechu sennego przyczyna nadcisnienia tetniczego i zaburzen rytmu serca. Opis przypadku.

A case of a 54-year-old man occupationally exposed to lead with diagnosed obstructive sleep apnea, hypertension and implanted artificial pacemaker due to atrioventricular dissociation of the third degree and pauses in sinus rhythm is presented.

[Individual protection devices--opinion and practice of occupational medicine physician]. / Srodki ochrony indywidualnej w aspekcie dzialalnosci lekarza medycyny pracy.

Technological developments have led to changes in work conditions and the character of work itself that modify the responsibilities and tasks of occupational medicine physicians. Their major task is to protect workers' health through primary prevention, which means the employment of all available measures to prevent adverse health effects resulting from working conditions unfavorable to human health. Statistical data on the incidence of occupational diseases and accidents at work in Poland show that despite many beneficial changes, better labor organization or new technologies in production and services, social and economic consequences of exposure-related diseases induced by so called hard harmful agents in the work environments are still the major problem, hence the significance of prevention. Activities aimed at preventing hazards at workplace should be carried out by employers, safety and work hygiene services and physicians involved in prophylactics. In addition, the selection and supply of individual protectors as well as their use by workers to protect themselves against dangerous and harmful factors occurring in the work environment play an essential role. The authors discuss the significance of using individual protectors from the viewpoint of occupational medicine physicians, and the tasks of this group of physicians in the light of epidemiology of occupational diseases induced by various agents present in the work environment.

Incidental stereotactic diagnosis of cerebral insults.

Among the patients (6854 patients 1990-1999) who underwent computer-assisted stereotactic biopsy most were referred with the presumptive diagnosis of a brain mass lesion. Forty-three cases (0.63%) were found in which the final histopathological diagnosis excluded a neoplastic, infectious or inflammatory lesion but disclosed a cerebral insult. Histologically these could be subdivided into ischemic insults in 38 cases (88%) and hemorrhagic insults in five cases (12%). On the basis of clinical and radiological findings in this group, 35 patients (81%) were sent to our department because of suspected neoplasmatic lesions, two patients (5%) because of multiple sclerosis, two patients (5%) because of inflammatory disease and one patient (2%) because of a suspected infectious parasitic disease. All patients underwent initial CT examinations which showed hypodense lesions of the brain in 38 patients (88%) and hyperdense lesions in five cases (12%). Constant enhancement on CT scans of the mass lesion was found in 12 patients (28%) only. Fourteen lesions (33%) were located in the right hemisphere, five lesions (12%) in the left hemisphere, nine lesions (21%) in the basal ganglia, four lesions (9%) in the midbrain, two lesions (4.5%) in the corpus callosum and one lesion (2%) in a thalamus. Multiple lesions were present in eight cases (19%). The most common initial neurological symptoms upon clinical presentation were hemiparesis (18 patients, 42%), epilepsy (eight patients, 18%), a change in mental status (six patients, 14%). There was no mortality and no operative morbidity associated with the stereotactic biopsy in this group of patients. The most common neurological disorder, cerebrovascular insult, rarely poses diagnostic problems. If there are doubts a serial stereotactic biopsy can safely clarify the situation.

The relation between cerebral blood flow velocities as measured by TCD and the incidence of delayed ischemic deficits. A prospective study after subarachnoid hemorrhage.

Patients (n = 127) with aneurysmal subarachnoid hemorrhage (SAH) were examined by transcranial Doppler ultrasonography (TCD) in a prospective study to follow the time course of the posthemorrhagic blood flow velocity in both the middle cerebral artery (MCA) and in the anterior cerebral artery (ACA). Results were analysed to reveal their relationship and predictive use with respect to the occurrence of delayed ischemic deficits. Mean flow velocities (MFV) higher than 120 cm sec(-1) in MCA and 90 cm sec(-1) in ACA were interpreted as indicative for significant vasospasm. In 20 of our 127 patients (16%) a delayed ischemic deficit (DID) was subsequently diagnosed clinically (DID+ group). Patients in the DID+ group can be characterized as those individuals who presented early during the observation period post-SAH with highest values of MFV, a faster increase and longer persistence of pathologically elevated MFV-values (exceeding 120 cm sec(-1) in MCA and 90 cm sec(-1) in ACA). They also show a greater difference in MFV-values if one compares the operated to the nonoperated side. Differences in MFV-values obtained in MCA or ACA were statistically significant (p < 0.05) for DID+ and DID- patients. The daily maximal increase of MFV was found between days 9 and 11 after SAH. In the DID+ group, the maximal MFV was 181 +/- 26 cm sec(-1) in MCA and 119 +/- 14 cm sec(-1) in ACA. In contrast to this, patients in the DID- group were found to present with MFV of 138 +/- 11 cm sec(-1) in MCA and 100 +/- 7 cm sec(-1) in ACA respectively. Delayed ischemic deficits appeared three times more often in DID+ patients than in patients with MFV < 120 cm sec(-1), if they showed a MFV > 120 cm sec(-1) in MCA. If pathological values were obtained in ACA, this ratio increases to about four times, if DID + patients presented with MFV > 90 cm sec(-1) versus patients with MFV < 90 cm sec(-1). Daily monitoring of vasospasm using TCD examination is thus helpful to identify patients at high risk for delayed ischemic deficits. This should allow us to implement further preventive treatment regimens.