Mitigating Oxidative Stress in Perinatal Cells: A Critical Step toward an Optimal Therapeutic Use in Regenerative Medicine

Abstract Oxidative stress (OS) occurs when the production of reactive oxygen species (ROS) is not balanced by the body’s antioxidant defense system. OS can profoundly affect cellular health and function. ROS can have a profound negative impact on cells that undergo a predestined and time-regulated process of proliferation or differentiation, such as perinatal stem cells. Due to the large-scale employment of these immunotolerant stem cells in regenerative medicine, it is important to reduce OS to prevent them from losing function and increase their application in the regenerative medicine field. This goal can be achieved through a variety of strategies, such as the use of antioxidants and other compounds that can indirectly modulate the antioxidant defense system by enhancing cellular stress response pathways, including autophagy and mitochondrial function, thereby reducing ROS levels. This review aims to summarize information regarding OS mechanisms in perinatal stem cells and possible strategies for reducing their deleterious effects. Oxidative stress (OS) occurs when the production of reactive oxygen species (ROS) is not balanced by the body’s antioxidant defense system. OS can profoundly affect cellular health and function. ROS can have a profound negative impact on cells that undergo a predestined and time-regulated process of proliferation or differentiation, such as perinatal stem cells. Due to the large-scale employment of these immunotolerant stem cells in regenerative medicine, it is important to reduce OS to prevent them from losing function and increase their application in the regenerative medicine field. This goal can be achieved through a variety of strategies, such as the use of antioxidants and other compounds that can indirectly modulate the antioxidant defense system by enhancing cellular stress response pathways, including autophagy and mitochondrial function, thereby reducing ROS levels. This review aims to summarize information regarding OS mechanisms in perinatal stem cells and possible strategies for reducing their deleterious effects

Perinatal Stem Cell Therapy to Treat Type 1 Diabetes Mellitus: A Never-Say-Die Story of Differentiation and Immunomodulation

Human term placenta and other postpartum-derived biological tissues are promising sources of perinatal cells with unique stem cell properties. Among the massive current research on stem cells, one medical focus on easily available stem cells is to exploit them in the design of immunotherapy protocols, in particular for the treatment of chronic non-curable human diseases. Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells and perinatal cells can be harnessed both to generate insulin-producing cells for beta cell replenishment and to regulate autoimmune mechanisms via immunomodulation capacity. In this study, the strong points of cells derived from amniotic epithelial cells and from umbilical cord matrix are outlined and their potential for supporting cell therapy development. From a basic research and expert stem cell point of view, the aim of this review is to summarize information regarding the regenerative medicine field, as well as describe the state of the art on possible cell therapy approaches for diabetes

Risk of SARS-CoV-2 infection and disease in metastatic triple-negative breast cancer patients treated with immune checkpoint inhibitors

Metastatic triple-negative breast cancer (mTNBC) is an aggressive disease with particularly poor outcomes [1]. Over the past few years, relevant gains in knowledge concerning the molecular landscape of this disease have allowed to considerably broaden the available therapeutic armamentarium. Poly ADP-ribose polymerase-1 inhibitors, epigenetic agents, anti-androgens, tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs) may all optimally exemplify the targeted therapeutic weapons recently gained in the fight against mTNBC [2]. Targeting of immune checkpoints through their respective monoclonal antibodies translates into effective antitumor responses not only in widely recognized ‘immunogenic’ tumor types, for example, melanoma and renal cell carcinoma, but also in other solid tumors including breast cancer [3]. PD-1 is an immune checkpoint expressed on the surface of B cells, T cells and natural killer T cells, with a critical role in modulating self tolerance, immune homeostasis and inflammation. When activated by PD-L1 or -L2, PD-1 mediates downregulation of T-cell activity, causes T-cell lysis and reduces cytokine production significantl

A case of 20-week abortion in a rare communicating rudimentary horn of a misinterpreted unicornuate uterus, incorrectly diagnosed as bicornuate: A serious hazard!

Female genital malformations, as the unicornuate uterus, are deviations from normal anatomy that could impair the reproductive potential of a woman or her health. We present a rare case of a 20-week spontaneous abortion in a 24 years old patient affected by a misunderstood unicornuate uterus with communicating rudimentary horn, previously diagnosed as bicornuate, and for this reason subjected to induction of abortive labor, using mifepristone and gemeprost. Following the ultrasound exam and MRI, performed due to the failure of the abortive procedure, revealed the diagnosis of unicornuate uterus with (not clear) communicating accessory horn pregnancy, then treated with laparotomy. 3D-ultrasonography, and above all MRI, should be performed in all those cases of suspected uterine anomalies, especially in presence of pregnancy or abortion, with the aim of avoiding wrong treatments, which leads to a high risk of uterine rupture. In this case, given the uncertainty of imaging exams performed in such an advanced second trimester of pregnancy, only the surgical approach was able to discover the real communication

Prognostic Relevance of Neutrophil to Lymphocyte Ratio (NLR) in Luminal Breast Cancer: A Retrospective Analysis in the Neoadjuvant Setting.

The neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A- or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR: 6.97, 95% CI: 1.65-10.55, p = 0.002) and OS (HR: 7.79, 95% CI: 1.25-15.07, p = 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67 ≥ 14% were also associated with worse DFS (p = 0.016, p = 0.002, and p = 0.001, respectively). In a multivariate analysis, luminal B subtype, post-treatment Ki67 ≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67 ≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT

Celector®: An Innovative Technology for Quality Control of Living Cells

Among the in vitro and ex vivo models used to study human cancer biology, cancer cell lines are widely utilized. The standardization of a correct tumor model including the stage of in vitro testing would allow for the development of new high-efficiency drug systems. The poor correlation between preclinical in vitro and in vivo data and clinical trials is still an open issue, hence the need for new systems for the quality control (QC) of these cell products. In this work, we present a new technology, Celector®, capable of the label-free analysis and separation of cells based on their physical characteristics with full preservation of their native properties. Two types of cancer cell lines were used: HL60 as cells growing in suspension and SW620 as adherent cells. Cell lines in general show a growth variability depending on the passage and method of culture. Celector® highlights physical differences that can be correlated to cell viability. This work demonstrates the use of Celector® as an analytical platform for the QC of cells used for drug screening, with fundamental improvement of preclinical tests. Cells with a stable doubling time under analysis can be collected and used as standardized systems for high-quality drug monitoring

Long-term outcome of breast cancer patients with pathologic N3a lymph node stage.

Abstract Purpose To evaluate factors influencing the long-term outcome of patients presenting with 10 or more metastatic axillary lymph nodes (pN3a) after surgery for primary breast cancer. Method Between January 1990 and December 2015, a total of 130 patients with pN3a breast cancer at surgery were identified in our Institutions and included in the study. Twenty-nine of them (22.3%) received neoadjuvant chemotherapy. The Multivariate Cox proportional hazards model was used to determine independent prognostic factors associated with DFS and OS. Results After a median follow-up of 6.4 years (range 0.87–25 years), 2 patients had a local relapse, 59 distant metastases (1 with local relapse) and 52 patients died. The 5-year DFS and OS rates were 61.8% and 71.5%, respectively. At multivariate analysis, pN3a stage after neoadjuvant chemotherapy (ypN3a) was significantly associated with increased risk of recurrence (HR 1.92, p = 0.02) and death (HR 2.05, p = 0.029). Absence of progesterone receptor (PR) expression was the most important tumor characteristic associated with poor prognosis, both in terms of recurrence (HR 2.55, p Conclusions The results of this study indicate that ypN3a stage, lack of expression of PR, and Ki-67 ≥ 20% negatively affect long-term outcome of patients with pN3a breast cancer

Fasting glucose and body mass index as predictors of activity in breast cancer patients treated with everolimus-exemestane: the EverExt study

Evidence on everolimus in breast cancer has placed hyperglycemia among the most common high grade adverse events. Anthropometrics and biomarkers of glucose metabolism were investigated in a observational study of 102 postmenopausal, HR + HER2- metastatic breast cancer patients treated with everolimus-exemestane in first and subsequent lines. Best overall response (BR) and clinical benefit rate (CBR) were assessed across subgroups defined upon fasting glucose (FG) and body mass index (BMI). Survival was estimated by Kaplan-Meier method and log-rank test. Survival predictors were tested in Cox models. Median follow up was 12.4 months (1.0-41.0). The overall cohort showed increasing levels of FG and decreasing BMI (p < 0.001). Lower FG fasting glucose at BR was more commonly associated with C/PR or SD compared with PD (p < 0.001). We also observed a somewhat higher BMI associated with better response (p = 0.052). More patients in the lowest FG category achieved clinical benefit compared to the highest (p < 0.001), while no relevant differences emerged for BMI. Fasting glucose at re-assessment was also predictive of PFS (p = 0.037), as confirmed in models including BMI and line of therapy (p = 0.049). Treatment discontinuation was significantly associated with changes in FG (p = 0.014). Further research is warranted to corroborate these findings and clarify the underlying mechanisms

Heterozygous Pathogenic Nonsense Variant in the ATM Gene in a Family with Unusually High Gastric Cancer Susceptibility

Germline pathogenic variants (PVs) in the Ataxia Telangiectasia mutated (ATM) gene (MIM* 607585) increase the risk for breast, pancreatic, gastric, and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. We describe a family presenting early-onset gastric cancer and harboring a heterozygous pathogenic ATM variant. The proband had gastric cancer (age 45) and reported a sister deceased due to diffuse gastric cancer (age 30) and another sister who developed diffuse gastric cancer (age 52) and ovarian serous cancer. Next generation sequencing for cancer susceptibility genes (APC, ATM, BRD1, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL1, SMAD4, STK11, and TP53) was performed. Molecular analysis identified the truncating c.5944C>T, p.(Gln1982*) variant in the ATM (NM_000051.3; NP_000042.3) in the proband. The variant had segregated in the living affected sister and in the unaffected daughter of the deceased affected sister. Familial early-onset gastric cancer is an unusual presentation for ATM-related malignancies. Individual variants may result in different specific risks. Genotype-phenotype correlations are challenging given the low penetrance and variable expressivity. Careful family history assessments are pivotal for prevention planning and are strengthened by the availability of molecular diagnoses

Fulvestrant and trastuzumab in patients with luminal HER2-positive advanced breast cancer (ABC): an Italian real-world experience (HERMIONE 9)

Purpose The most appropriate therapy for HR+/HER2-positive (HER2+) advanced breast cancer (ABC) is a matter of debate. Co-targeting of both receptors represents an attractive strategy to overcome the cross-talk between them. Methods The HERMIONE 9 is an observational retrospective multicentric study which aimed to describe the clinical outcome of patients with HR+/HER2+ABC who received the combination of Fulvestrant (F) and Trastuzumab (T) as part of their routine treatment at 10 Italian Institutions. Results Eighty-seven patients were included. Median age was 63 (range, 35–87) years. The median number of previous treatments was 3 (range, 0–10) and F and T were administered as≥3rd line in 67 patients. Among the 86 evaluable patients, 6 (6.9%) achieved CR, 18 (20.7%) PR, and 44 (50.6%) had SD ≥24 weeks with an overall CBR of 78.2%. At a median follow-up of 33.6 months, mPFS of the entire cohort was 12.9 months (range, 2.47–128.67). No diference was observed in mPFS between patients treated after progression or as maintenance therapy (mPFS 12.9 and 13.9 months in 64 and 23 patients, respectively), neither considering the number of previous treatment lines (≤3 or<3). Conclusion The combination of F and T was active in this cohort at poor prognosis and deserves further investigations possibly in combination with pertuzumab in patients with high ER expression