OBJECTIVE: Fibroblast growth factors (FGFs) are a family of 22 proteins and 4 FGF receptors (FGFRs) that are crucial elements for normal development. The contribution of different FGFs and FGFRs for the homeostasis or disease of the cartilage from the mandibular condyle is unknown. Therefore, our goal was to characterize age-related alterations in the protein expression of FGF ligands and FGFRs in the mandibular condyle of mice.
METHODS: Mandibular condyles of 1-, 6-, 12-, 18-, and 24-month-old C57BL/6J male mice (5 per group) were collected and histologically sectioned. Immunofluorescence for FGFs that have been reported to be relevant for chondrogenesis (FGF2, FGF8, FGF9, FGF18) as well as the activated/phosphorylated FGFRs (pFGFR1, pFGFR3) was carried out.
RESULTS: FGF2 and FGF8 were strongly expressed in the cartilage and subchondral bone of 1-month-old mice, but the expression shifted mainly to the subchondral bone as mice aged. FGF18 and pFGFR3 expression was limited to the cartilage of 1-month-old mice only. Meanwhile, pFGFR1 and FGF9 were mostly limited to the cartilage with a significant increase in expression as mice aged.
CONCLUSIONS: Our results indicate FGF2 and FGF8 are important growth factors for mandibular condylar cartilage growth in young mice but with limited role in the cartilage of older mice. In addition, the increased expression of pFGFR1 and FGF9 and the decreased expression of pFGFR3 and FGF18 as mice aged suggest the association of these factors with aging and osteoarthritis of the cartilage of the mandibular condyle.

Despite its relative low incidence, PDAC is one of the most aggressive and lethal types of cancer, being currently the seventh leading cause of cancer death worldwide, with a 5-year survival rate of 10.8%. Taking into consideration the necessity to improve the prognosis of these patients, this research has been focused on the discovery of new biomarkers. For this purpose, patients with BL and resectable disease were recruited. Serum cytokines and growth factors were monitored at different time points using protein arrays. Immune cell populations were determined by flow cytometry in peripheral blood as well as by immunohistochemistry (IHC) in tumor tissues. Several cytokines were found to be differentially expressed between the study subgroups. In the BL disease setting, two different scores were proven to be independent prognostic factors for progression-free survival (PFS) (based on IL-10, MDC, MIF, and eotaxin-3) and OS (based on eotaxin-3, NT-3, FGF-9, and IP10). In the same context, CA19-9 was found to play a role as independent prognostic factor for OS. Eotaxin-3 and MDC cytokines for PFS, and eotaxin-3, NT-3, and CKβ8-1 for OS, were shown to be predictive biomarkers for nab-paclitaxel and gemcitabine regimen. Similarly, oncostatin, BDNF, and IP10 cytokines were proven to act as predictive biomarkers regarding PFS, for FOLFIRINOX regimen. In the resectable cohort, RANTES, TIMP-1, FGF-4, and IL-10 individually differentiated patients according to their cancer-associated survival. Regarding immune cell populations, baseline high levels of circulating B lymphocytes were related to a significantly longer OS, while these levels significantly decreased as progression occurred. Similarly, baseline high levels of helper lymphocytes (CD4+), low levels of cytotoxic lymphocytes (CD8+), and a high CD4/CD8 ratio, were related to a significantly longer PFS. Finally, high levels of CD4+ and CD8+ intratumoural infiltration was associated with significantly longer PFS. In conclusion, in this study we were able to identify several prognostic and predictive biomarker candidates in patients diagnosed of resectable or BL PDAC.

In Multiple Myeloma (MM) the finely tuned homeostasis of the bone marrow (BM) microenvironment is disrupted. Evasion of programmed cell death (apoptosis) represents a hallmark of cancer. Besides genetic aberrations, the supportive and protective MM BM milieu, which is constituted by cytokines and growth factors, intercellular and cell: extracellular matrix (ECM) interactions and exosomes, in particular, plays a key role in the abundance of pro-survival members of the Bcl-2 family (i.e., Mcl-1, Bcl-2, and Bcl-xL) in tumor cells. Moreover, microenvironmental cues have also an impact on stability- regulating post-translational modifications of anti-apoptotic proteins including de/phosphorylation, polyubiquitination; on their intracellular binding affinities, and localization. Advances of our molecular knowledge on the escape of cancer cells from apoptosis have informed the development of a new class of small molecules that mimic the action of BH3-only proteins. Indeed, approaches to directly target anti-apoptotic Bcl-2 family members are among today\'s most promising therapeutic strategies and BH3-mimetics (i.e., venetoclax) are currently revolutionizing not only the treatment of CLL and AML, but also hold great therapeutic promise in MM. Furthermore, approaches that activate apoptotic pathways indirectly via modification of the tumor microenvironment have already entered clinical practice. The present review article will summarize our up-to-date knowledge on molecular mechanisms by which the MM BM microenvironment, cytokines, and growth factors in particular, mediates tumor cell evasion from apoptosis. Moreover, it will discuss some of the most promising science- derived therapeutic strategies to overcome Bcl-2- mediated tumor cell survival in order to further improve MM patient outcome.

Retinopathy of prematurity (ROP) is the main risk factor for vision-threatening disease in premature infants with low birth weight. An accumulating number of independent studies have focused on ROP pathogenesis and have demonstrated that laser photocoagulation therapy and/or anti-VEGF treatment are effective. However, early diagnosis of ROP is still critical. At present, the main method of ROP screening is based on binocular indirect ophthalmoscopy. However, the judgment of whether ROP occurs and whether treatment is necessary depends largely on ophthalmologists with a great deal of experience. Therefore, it is essential to develop a simple, accurate and effective diagnostic method. This review describes recent findings on novel biomarkers for the prediction, diagnosis and prognosis of ROP patients. The novel biomarkers were separated into the following categories: metabolites, cytokines and growth factors, non-coding RNAs, iconography, gut microbiota, oxidative stress biomarkers, and others. Biomarkers with high sensitivity and specificity are urgently needed for the clinical applications of ROP. In addition, using non-invasive or minimally invasive methods to obtain samples is also important. Our review provides an overview of potential biomarkers of ROP.

Late-onset Alzheimer\'s disease (AD) has a significant genetic and immunological component, but the molecular mechanisms through which genetic and immunity-related risk factors and their interplay contribute to AD pathogenesis are unclear. Therefore, we screened for genetic sharing between AD and the blood levels of a set of cytokines and growth factors to elucidate how the polygenic architecture of AD affects immune marker profiles. For this, we retrieved summary statistics from Finnish genome-wide association studies of AD and 41 immune marker blood levels and assessed for shared genetic etiology, using a polygenic risk score-based approach. For the blood levels of 15 cytokines and growth factors, we identified genetic sharing with AD. We also found positive and negative genetic concordances-implying that genetic risk factors for AD are associated with higher and lower blood levels-for several immune markers and were able to relate some of these results to the literature. Our results imply that genetic risk factors for AD also affect specific immune marker levels, which may be leveraged to develop novel treatment strategies for AD.

Non-thermal atmospheric pressure plasma (NTAPP) has been reported to induce wound healing, activation of immune cells, and proliferation of mesoderm-derived adult stem cells in human. However, the mechanism by which NTAPP activates these physiological effects is poorly understood. Here, we examined whole genome expression profiles of adipose tissue-derived stem cells (ASCs), the proliferation of which is induced by NTAPP. NTAPP upregulated the expression of genes for cytokine and growth factor, but downregulated genes in apoptotic pathways. When ASCs were treated with NTAPP in the presence of a nitric oxide (NO) scavenger, the expression of various cytokines and growth factors decreased, suggesting that NO is primarily responsible for the enhanced cytokine and growth factor expression induced by NTAPP. Increased histone deacetyl transferase 1 (HDAC1) and decreased acetylated histone 3 were detected in NTAPP-treated ASCs. Similarly, ASCs pre-treated with HDAC, DNA methylation, or histone methylation inhibitors had reduced expression of cytokines and growth factors after NTAPP treatment. Taken together, these results strongly suggest that NTAPP induces epigenetic modifications that activate the expression of cytokines and growth factors, explaining how NTAPP acts as an efficient tool in regenerative medicine to stimulate stem cell proliferation, to activate immune cells, and to recover wounds.

Chronic wounds, such as pressure ulcers, are a common complication of impaired peripheral circulation, such as in advanced diabetes. Factors secreted by mesenchymal stromal cells (MSCs) have been shown to enhance wound healing in vitro and in vivo. However, there is little understanding of the impact of the chronic wound environment, namely the limited supply of nutrients and oxygen, on the ability of wound cells to respond to MSCs. In this study, we first established the effects of hypoxia (1% O2) and low serum (1% serum) concentration on the proliferation and migration of keratinocytes. We found that hypoxia and low serum significantly slowed down these processes. Next, we found that supplementation with human MSC-concentrated conditioned media (hMSC-CM) enhanced both cell migration and proliferation in the presence of hypoxia and low serum. Furthermore, low serum and hypoxia decreased cell spreading and F-actin expression, which was reversed in the presence of hMSC-CM. Several wound healing mediators were identified in hMSC-CM, including IL-5, IL-6, IL-8, IL-9, IP-10, MCP-1, FGF-2, and VEGF. This study suggests that the concentrated secretome of human MSCs can reverse the inhibitory effect of hypoxia and low serum on keratinocyte proliferation and migration. This phenomenon may contribute to the beneficial effects of hMSC-CM on wound healing in vivo.

Aim In the osteoarthritis (OA) disease, all structures of the joint are involved. The infrapatellar Hoffa fat pad is rich in macrophages and granulocytes, which also represents a source of adipose mesenchymal progenitor cells (ASC) cells. In our study, we analyze how OA affects the ability of ASC-derived from Hoffa\'s fat pad to differentiate into chondrocytes. Material and methodology We took knee Hoffa\'s pad samples and adipose tissue from the proximal thigh from 6 patients diagnosed with severe OA and from another 6 patients with an anterior cruciate ligament (ACL) rupture without OA. From all the patients, we took subcutaneous adipose tissue from the thigh, as the control group. Samples of synovial fluid (SF) were also extracted. The gene expression was analyzed by real-time quantitative polymerase chain reaction. Results PTH1R and MMP13 expression during chondrogenic differentiation were similar between OA and ACL groups, while the expression of OPG, FGF2, TGFβ, MMP3 were significantly lower in the OA group. Exposure of differentiated ASC to OA SF induced an increase in the expression of OPG, PTH1R, and MMP13 and a decrease in the expression of FGF2 in cell culture of the ACL group. However, expression of none of these factors was altered by the OA synovial fluid in ASC cells of the OA group. Conclusion OA of the knee also affects the mesenchymal stem cells of Hoffa fat, suggesting that Hoffa fat is a new actor in the OA degenerative process that can contribute to the origin, onset, and progression of the disease.

There is a growing interest in low-grade inflammatory and metabolic alterations in patients with chronic schizophrenia (SCH).
Inflammatory (tumor-necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukins [IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10], monocyte chemo-attractant protein-1 [MCP-1]) and growth factors (vascular endothelial growth factor [VEGF], epidermal growth factor [EGF]) were measured in blood serum samples of 105 SCH patients and 148 control subjects (CS). Simultaneously the clinical biomarkers (C-reactive protein [CRP], triglycerides [TG], low-density lipoprotein [LDL-c] and high-density lipoprotein [HDL-c] cholesterol, glycated hemoglobin [HbA1c]) were measured, and body mass index (BMI) was calculated for patients.
Several cyto-/chemokines (IFN-γ, MCP-1, IL-2, IL-6, IL-8 and IL-10) were significantly (P<0.0000001) elevated in SCH patients compared to CS. Odds ratios, obtained from logistic regression analyses, were significantly elevated for IL-2, IL-6, IL-10, INF-γ, and decreased for TNF-α in SCH group. Among the patients, higher IL-2, IL-6, INF-γ and lower MCP-1 levels as well as male gender were together significant (P<0.000001) predictors of higher HbA1c levels, and TG/HDL-c parameter was associated with ratios of INF-γ/IL-10 (P=0.004), and INF-γ/IL-4 (P=0.049), HbA1c (P=0.005), INF-γ (P=0.009), as well as LDL-c (P=0.02) levels.
IL-2, IL-6, IL-10 and IFN-γ were the most significant SCH-related markers among the measured cytokines in our patient group. Furthermore, significant associations between pro-/anti-inflammatory imbalance and HbA1c as well as cardio-metabolic risk marker (TG/HDL-c) were observed, indicating higher risks of diabetes and cardiovascular diseases among SCH patients.

OBJECTIVE: The purpose of this study was to assess the effect(s) of platelet-rich plasma (PRP) on osteochondral donor site healing in a rabbit model.
METHODS: Osteochondral donor sites 3 mm in diameter and 5 mm in depth were created bilaterally on the femoral condyles of 12 New Zealand White rabbits. Knees were randomized such that one knee in each rabbit received an intra-articular injection of PRP and the other received saline (placebo). Rabbits were euthanized at 3, 6, and 12 weeks following surgery. Repair tissue was evaluated using the International Cartilage Repair Society (ICRS) macroscopic and histological scores.
RESULTS: No complications occurred as a result of the interventions. There was no significant difference in macroscopic scores between the 2 groups (5.5 ± 3.8 vs. 3.8 ± 3.5; P = 0.13). Subjective macroscopic assessment determined greater tissue infill with fewer fissures and a more cartilage-like appearance in PRP-treated knees. Overall ICRS histological scores were better in the PRP group compared with the placebo (9.8 ± 2.0 vs. 7.8 ± 1.8; P = 0.04). Histological scores were also higher in the PRP group compared with the placebo group at each time point. Greater glycosaminoglycan and type II collagen content were noted in the repair tissue of the PRP group compared with the placebo group.
CONCLUSIONS: The results of this study indicate that PRP used as an intra-articular injection may improve osteochondral healing in a rabbit model.