Combined Anti-PD-1 and Anti-CTLA-4 Treatment in Stage IV Melanoma Patients: A Bicentric Analysis of Real-World Data and a Modern Treatment Scenario Proving Lactate Dehydrogenase's Usefulness.

BACKGROUND: This retrospective study evaluates patients with stage IV melanoma treated with nivolumab and ipilimumab combination therapy from two regional oncology centers in Romania from the year 2019 to the end of 2022. METHODS: The data were analyzed in SAS for Windows, V9.4. LDH means were stratified by the number of metastatic sites before treatment and compared using an independent sample T-test. The survival curves were estimated using the Kaplan-Meier method, and the survival distributions were compared with the log-rank test. The effects of the main clinical and pathological variables on OS and PFS were investigated with Cox regression. RESULTS: The LDH mean for patients with three or more metastases before treatment was significantly higher than that for patients with only one metastatic site. The Kaplan-Meier curve of OS in all evaluable patients enrolled in the study resulted in a median OS of 346 days (95% CI: 150) and a median PFS of 211 days (95% CI: 113-430). A total of 45.3% of the patients experienced adverse events during the nivolumab + ipilimumab treatment, with some of them having multiple organ systems involved. DISCUSSION: The OS values were lower than those reported in approved clinical trials, but the results show a marked improvement when compared to the results obtained by chemotherapy regimens previously used in these scenarios. CONCLUSION: This study provides real-world insights into the survival data and safety profiles of combination therapy with anti-PD-1 antibodies and anti-CTLA-4 antibodies.

Immunologic reactions to bone and articular implants.

BACKGROUND: In recent years the number on implantable devices that have been used in orthopedic surgeries has increased exponentially. As the number of people with orthopedic implants has grown, implant failure has become an increasingly important public health issue. While a significant percent of joint implants fails at between 15 and 20 years some authors suggest that one of the main causes is the interaction between the immune system of the host and the material of the implant METHODS: The search engines used for research comprised of PubMed, Google Scholar and Cochrane Library. RESULTS: This review aims to summarize relevant and recent data on the immune reactions that are taking place at the juxtaposition between the implant and the patient's tissue, the time frame in which these immune reactions take place and some of the factors that can influence this reaction. The immune reactions can be divided into: hyperacute immune reactions (anaphylactic shock), acute reactions, the transition between the acute phase and the chronic phase and last but not least chronic immune reactions to such implants. CONCLUSION: The research being done with regard to implant-related immunology strives to help in solving the problem of long-term implant failure.

The Influence of Thyroid Pathology on Osteoporosis and Fracture Risk: A Review.

Thyroid hormones are important factors that regulate metabolism and cell differentiation throughout the human body. A complication of thyroid pathology is represented by an alteration of the bone metabolism which can lead to osteoporosis and fragility fractures, known to have a high mortality rate. Although there is a consensus on the negative impact of hyperthyroidism on bone metabolism, when referring to hypothyroidism, subclinical hypothyroidism, or subclinical hyperthyroidism, there is no general agreement. The aim of our review was to update clinicians and researchers about the current data regarding the bone health in hypothyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism patients. Thyroid disorders have an important impact on bone metabolism and fracture risk, such that hyperthyroidism, hypothyroidism, and subclinical hyperthyroidism are associated with a decreased bone mineral density (BMD) and increased risk of fracture. Subclinical hypothyroidism, on the other hand, is not associated with osteoporosis or fragility fractures, and subclinical hyperthyroidism treatment with radioiodine could improve bone health.

Senescence-induced immunophenotype, gene expression and electrophysiology changes in human amniocytes.

The aim of the study was to evidence replicative senescence-induced changes in human amniocytes via flow cytometry, quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) and automated/manual patch-clamp. Both cryopreserved and senescent amniocytes cultured in BIO-AMF-2 medium featured high percentages of pluripotency cell surface antigens SSEA-1, SSEA-4, TRA1-60, TRA1-81 (assessed by flow cytometry) and expression of pluripotency markers Oct4 (Pou5f1) and Nanog (by qRT-PCR). We demonstrated in senescent vs cryopreserved amniocytes decreases in mesenchymal stem cell surface markers. Senescence-associated ß-galactosidase stained only senescent amniocytes, and they showed no deoxyuridine incorporation. The gene expression profile revealed a secretory phenotype of senescent amniocytes (increased interleukin (IL)-1α, IL-6, IL-8, transforming growth factor ß, nuclear factor κB p65 expression), increases for cell cycle-regulating genes (p16INK4A ), cytoskeletal elements (ß-actin); HMGB1, c-Myc, Bcl-2 showed reduced changes and p21, MDM2 decreased. Via patch-clamp we identified five ion current components: outward rectifier K+ current, an inactivatable component, big conductance Ca2+ -dependent K+ channels (BK) current fluctuations, Na+ current, and inward rectifier K+ current. Iberiotoxin 100 nmol/L blocked 71% of BK fluctuations, and lidocaine 200 µmol/L exerted use-dependent Na+ current block. Transient receptor potential (TRP)M7-like current density at -120 mV was significantly increased in senescent amniocytes. The proinflammatory profile acquired by senescent amniocytes in vitro may prevent their use in clinical therapies for immunosuppression, antiapoptotic and healing effects.

Advanced glycation end products, oxidative stress and metalloproteinases are altered in the cerebral microvasculature during aging.

Biological aging is associated with an increased incidence of cerebrovascular disease. Recent findings indicate that oxidative stress promoting age-related changes of cerebral circulation are involved in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease. The aim of this study was to evaluate the contribution of cerebral microvessels to the oxidative stress during brain aging, by: (i) assessment of precursors for advanced glycation end products (AGE) formation, (ii) activities of antioxidant enzymes, namely superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione disulfide reductase (GR), and (iii) the activities of metalloproteinases (MMPs), MMP-2 and MMP-9, involved in synaptogenesis and memory consolidation. The experiments were performed on two groups of male Wistar rats: 15 young (3-6 months old) and 15 aged (18-24 months old) animals. The cerebral microvessels were isolated by mechanical homogenization, the concentration of protein carbonyls and the activity of antioxidant enzymes were evaluated by spectrophotometry, and gelatin SDS-PAGE zymography was employed to evaluate MMP-2 and MMP-9 activities. The results showed that, by comparison with young rats, aged brain microvessels contain: (i) approximately 106 % increase of protein carbonyls production; (ii) approximately 68% higher GPx activity, unmodified activities of SOD and GR; (iii) approximately 30% diminishment in MMP-2 activity, and the specific occurrence of MMP-9 enzyme. The data suggest that the age-related changes of microvessels could increase the propensity for cerebral diseases and might represent, at least in part, a prerequisite for the deterioration of mental and physical status in the elderly.

Inhibitory effect of acetylsalicylic acid on matrix metalloproteinase - 2 activity in human endothelial cells exposed to high glucose.

Matrix metalloproteinases play a major role in the process of angiogenesis, an important feature of diabetes complications, cancer or rheumatoid arthritis. High glucose concentrations were reported to augment metalloproteinase-2 secretion in some cell types. In the present study we investigated the influence of acetylsalicylic acid on metalloproteinase- 2 secretion and expression in endothelial cells cultured for one week in high glucose conditions (25 mM and 33 mM). Metalloproteinase-2 activity was evidenced by gel zymography, the protein was identified by Western blotting, and the gene expression was quantitated by RT-PCR. The results indicated a marked inhibitory effect of acetylsalicylic acid at gene expression level (approximately 43%) and also at secretion level in samples of conditioned media (approximately 30%) and cellular homogenates (approximately 70%). This may suggest that acetylsalicylic acid could have a beneficial effect in preventing the angiogenic process that appears in diabetes complications.