Cell Proliferation Growth Research Articles

Chronic mucocutaneous candidiasis, mycobacterial infections and rosacea in a Mexican adult with STAT1 gain of function

STAT1 is a cytoplasmic transcription factor associated with cell growth regulation, differentiation, proliferation, metabolism, and apoptosis. IFN-mediated JAK/STAT signaling pathway is involved in eliminating intracellular pathogens and viruses. However, pathogenic variants in STAT1 can result in impaired or increased function. Increased activity or function in STAT1 was described in 2011 and is characterized by excessive phosphorylation of the transcription factor. Carriers can develop autoimmune and inflammatory diseases and are susceptible to fungal, viral, and bacterial infections. The early and common manifestation is chronic mucocutaneous candidiasis. Here, we report a clinical case of a patient with increased STAT1 activity or gain of function, which started in the first year of his life. He is currently 27 years old and has presented bacillus Calmette-Guérin and Mycobacterium tuberculosis infection, chronic mucocutaneous candidiasis, tinea capitis, and facial and ocular rosacea. HIV infection was ruled out. Given the clinical manifestations, an inborn error of immunity was suspected, specifically STAT1 with gain of function. The diagnosis was corroborated by the sequencing of multiple genes associated with inborn errors of immunity. The pathogenic variant c.961A>G (p.Arg321Gly) in the STAT1 gene, previously reported as a gain of function mutation, was found in the patient. Finally, this case illustrates that mutations in immune-associated genes can contribute to producing severe and recurrent infections, even in adult patients. Chronic mucocutaneous candidiasis should raise suspicion of gain of function in STAT1.

Immunosuppressive SOX9-AS1 Resists Triple-Negative Breast Cancer Senescence Via Regulating Wnt Signalling Pathway.

Long noncoding RNAs (lncRNAs) are involved in the regulation of triple-negative breast cancer (TNBC) senescence, while pro-carcinogenic lncRNAs resist senescence onset leading to the failure of therapy-induced senescence (TIS) strategy, urgently identifying the key senescence-related lncRNAs (SRlncRNAs). We mined seven SRlncRNAs (SOX9-AS1, LINC01152, AC005152.3, RP11-161 M6.2, RP5-968 J1.1, RP11-351 J23.1 and RP11-666A20.3) by bioinformatics, of which SOX9-AS1 was reported to be pro-carcinogenic. Invitro experiments revealed the highest expression of SOX9-AS1 in MDA-MD-231 cells. SOX9-AS1 knockdown inhibited cell growth (proliferation, cycle and apoptosis) and malignant phenotypes (migration and invasion), while SOX9-AS1 overexpression rescued these effects. Additionally, SOX9-AS1 knockdown facilitated tamoxifen-induced cellular senescence and the transcription of senescence-associated secretory phenotype (SASP) factors (IL-1α, IL-1β, IL-6 and IL-8) mechanistically by resisting senescence-induced Wnt signal (GSK-3β/β-catenin) activation. Immune infiltration analysis revealed that low SOX9-AS1 expression was accompanied by a high infiltration of naïve B cells, CD8+ T cells and γδ T cells. In conclusion, SOX9-AS1 resists TNBC senescence via regulating the Wnt signalling pathway and inhibits immune infiltration. Targeted inhibition of SOX9-AS1 enhances SASP and thus mobilises immune infiltration to adjunct TIS strategy.

Ketogenic diet enhances the anti-cancer effects of PD-L1 blockade in renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is characterized by a predominant metabolic reprogramming triggering energy production by anaerobic glycolysis at the expense of oxydative phosphorylation. Ketogenic diet (KD), which consists of high fat and low carbohydrate intake, could bring required energy substrates to healthy cells while depriving tumor cells of glucose. Our objective was to evaluate the effect of KD on renal cancer cell tumor metabolism and growth proliferation. Growth cell proliferation and mitochondrial metabolism of ACHN and Renca renal carcinoma cells were evaluated under ketone bodies (KB) exposure. In vivo studies were performed with mice (nude or Balb/c) receiving a xenograft of ACHN cells or Renca cells, respectively, and were then split into 2 feeding groups, fed either with standard diet or a 2:1 KD ad libitum. To test the effect of KD associated to immunotherapy, Balb/c mice were treated with anti-PDL1 mAb. Tumor growth was monitored. In vitro, KB exposure was associated with a significant reduction of ACHN and Renca cell proliferation and viability, while increasing mitochondrial metabolism. In mice, KD was associated with tumor growth reduction and PDL-1 gene expression up-regulation. In Balb/c mice adjuvant KD was associated to a better response to anti-PDL-1 mAb treatment. KB reduced the renal tumor cell growth proliferation and improved mitochondrial respiration and biogenesis. KD also slowed down tumor growth of ACHN and Renca in vivo. We observed that PDL-1 was significantly overexpressed in tumor in mice under KD. Response to anti-PDL-1 mAb was improved in mice under KD. Further studies are needed to confirm the therapeutic benefit of adjuvant KD combined with immunotherapy in patients with kidney cancer.

High histone crotonylation modification in bovine fibroblasts promotes cell proliferation and the developmental efficiency of preimplantation nuclear transfer embryos

Lysine crotonylation (Kcr) is a recently discovered histone acylation modification that is closely associated with gene expression, cell proliferation, and the maintenance of stem cell pluripotency and indicates the transcriptional activity of genes and the regulation of various biological processes. During cell culture, the introduction of exogenous croconic acid disodium salt (Nacr) has been shown to modulate intracellular Kcr levels. Although research on Kcr has increased, its role in cell growth and proliferation and its potential regulatory mechanisms remain unclear compared to those of histone methylation and acetylation. Our investigation demonstrated that the addition of 5 mM Nacr to cultured bovine fibroblasts increased the expression of genes associated with Kcr modification, ultimately promoting cell growth and stimulating cell proliferation. Somatic cell nuclear transfer of donor cells cultured in 5 mM Nacr resulted in 38.1% blastocyst development, which was significantly greater than that in the control group (25.2%). This research is important for elucidating the crotonylation modification mechanism in fibroblast proliferation to promote the efficacy of somatic cell nuclear transfer.

Research on the Effect and Mechanism of Selenium on Colorectal Cancer Through TRIM32.

The intake of selenium (Se) in the human body is negatively correlated with the risk of colorectal cancer (CRC), but its mechanism in the occurrence and development of CRC is not clear. This study aimed to evaluate the therapeutic effect of Se on CRC, and explore the anti-tumor effect of Se supplementation on CRC and its molecular mechanism. In this study, we utilized colony formation assay, cell scratch test, Transwell migration, and flow cytometry to assess cell proliferation, migration, and apoptosis. Our findings demonstrate that Se effectively suppresses the growth and proliferation of CRC cell lines HCT116 and SW480 and promoting cellular apoptosis. In vivo experiments demonstrated a significant inhibitory effect of Se on tumor growth. CRC-related datasets were extracted from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases for differential expression analysis of TRIM32 and survival analysis. We found that TRIM32 was highly expressed in tumor tissues of CRC patients and correlated with a poor prognosis. Furthermore, through RNA sequencing analysis, we identified TRIM32 as a gene that was significantly decreased after Se treatment in HCT116 cells. This finding was subsequently validated by Western blot results. Moreover, TRIM32 knockdown combined with Se treatment significantly inhibited cell growth proliferation and migration and further induced apoptosis of colorectal cancer cells. In conclusion, our findings provided evidence that Se inhibited the growth of colorectal cancer cells by down-regulating TRIM32.

Abstract 5742: Therapeutic efficacy of CA102N in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a challenging cancer to treat due to its aggressive nature and late-stage diagnosis. Considering the lack of effective therapies, there is an urgent need to develop new and effective therapeutics to improve the prognosis of patients. CA102N is a carrier-mediated novel anticancer product where hyaluronic acid is conjugated to Nimesulide-NH2. CA102N is currently under development for the treatment of solid tumors, including colorectal cancer. CA102N was safe and well tolerated in the first-in-human trial in patients with locally advanced or metastatic solid tumors. In the present study, the in vitro anticancer activity of CA102N was investigated in K-ras mutant PANC-1 pancreatic cancer cells. The antitumor efficacy was also tested in vivo in the PANC-1 mice model. Results demonstrated that CA102N inhibits cell growth, cell migration, angiogenesis, and cell proliferation in both K-ras mutant PANC-1 pancreatic cancer cells or tumors. Administration of CA102N in PANC-1 xenografts resulted in a dose-dependent and statistically significant decrease in tumor growth at 9.8 mg/kg and 14.7 mg/kg Nim equivalents, respectively, compared to the vehicle control group. A significant decrease (80%) in liver metastasis was also noted in the PANC-1 orthotopic mice model at 19.6 mg/kg Nim equivalents dose level. Mechanistically, CA102N was found to suppress the PI3k/Akt/mTOR and Raf/MEK/ERK signaling pathways, in addition to reducing the expressions of the N6-methyladenosine (m6A) reader and writer proteins, OCT3/4 transcription factor and RAS levels in vivo. CA102N also modified the tumor stroma and improved drug permeability in vivo. Based on this compelling data, CA102N shows promise as a potential treatment for pancreatic cancer. Combination therapies and regimens are currently being explored in in vivo models as a strategy for clinical development. Citation Format: Louis Lin, Shuling Tu, Eskouhie Tchaparian. Therapeutic efficacy of CA102N in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5742.

Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient.

The pathophysiology of nonketotic hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neural model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance, and protein analyses. This study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Our analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology of nonketotic hyperglycinemia and offer new perspectives for therapeutic options.

Natural Coumarin Derivatives Targeting Melanoma.

In general, a cancerous process starts from uncontrolled cell growth, apoptosis, and rapid proliferation of cellular clones, as well as, reactive oxygen species (ROS) and imbalance of ROS-antioxidant production also could be involved in the genesis of the disease. Cancer has accounted for millions of deaths worldwide every year, representing a relevant threat to human lives. In this context, malignant melanoma represents the most aggressive and deadliest type of cancer, leading to increased rates of patient deaths. Natural active compounds have demonstrated their pharmacological benefits in several different studies. Among these compounds, coumarin analogs have demonstrated promising biological profiles, considering their efficacy and low toxicity. In this context, this phytochemical oxygenated core has been broadly investigated since it presents several biological properties of interest in the medicinal field. Herein, we reported a complete compilation of studies focused on natural coumarins against melanoma, as well as, tyrosinase since it is a cooper-catalyzed oxidase that performs an essential role during melanogenesis (Eu-melanins and Pheo-melanins), which is associated with melanoma. Thus, three different subclasses of natural coumarin were described in detail, such as simple coumarin core, furanocoumarins, pyranocoumarins, and pyrone-substituents. Additionally, insights on tyrosinase have been provided, allowing an overview of some structural/functional aspects of its enzyme, such as the presence of a binuclear type 3 cooper coordination at the binding site of this target, acting as cofactors. Posteriorly, several coumarin-based analogs with anti-tyrosinase activity also were reported and discussed. Finally, we believe that unprecedented review can be a valuable source of information, which can be used to design and develop novel coumarin-based analogs targeting melanoma and also tyrosinase enzyme, contributing to the advances in the field of natural products.

3D human stem-cell-derived neuronal spheroids for in vitro neurotoxicity testing of methylglyoxal, highly reactive glycolysis byproduct and potent glycating agent

Human-derived three-dimensional (3D) in vitro models are advanced human cell-based model for their complexity, relevance and application in toxicity testing. Intracellular accumulation of methylglyoxal (MGO), the most potent glycating agent in humans, mainly generated as a by-product of glycolysis, is associated with age-related diseases including neurodegenerative disorders.In our study, 3D human stem-cell-derived neuronal spheroids were set up and applied to evaluate cytotoxic effects after short-term (5 to 48 h) treatments with different MGO concentrations, including low levels, taking into consideration several biochemical endpoints.In MGO-treated neurospheroids, reduced cell growth proliferation and decreased cell viability occurred early from 5-10 μM, and their compactness diminished starting from 100 μM, apparently without affecting spheroid size. MGO markedly caused loss of the neuronal markers MAP-2 and NSE from 10-50 μM, decreased the detoxifying Glo1 enzyme from 50 μM, and activated NF-kB by nuclear translocation.The cytochemical evaluation of the 3D sections showed the presence of necrotic cells with loss of nuclei. Apoptotic cells were observed from 50 μM MGO after 48 h, and from 100 μM after 24 h. MGO (50–10 µM) also induced modifications of the cell–cell and cell-ECM interactions. These effects worsened at the higher concentrations (300–500 µM).In 3D neuronal spheroids, MGO tested concentrations comparable to human samples levels measured in MGO-associated diseases, altered neuronal key signalling endpoints relevant for the pathogenesis of neurodegenerative diseases and aging. The findings also demonstrated that the use of 3D neuronal spheroids of human origin can be useful in a strategy in vitro for testing MGO and other dicarbonyls evaluation.

193 Creatine Monohydrate on In Vitro Cultivated Bovine Cells Leading to Guanidinoacetic Acid Supplementation In Vivo

Abstract Guanidinoacetic acid (GAA) is an amino acid-like compound that acts as a precursor to creatine (CRE) when either made in the body or digested. Creatine is directly used by skeletal muscle tissue as an energy source with the potential to act as a growth-promoting agent. The study objectives were to evaluate the effects of various CRE concentrations on bovine satellite cells for the rate of proliferation and myogenic differentiation. Satellite cells (SC) were isolated from the Longissimus muscle of 3-month-old Holstein bulls (n = 5). Cells were seeded at a density of 1 × 104 cells/mL on 96-well plates and incubated with 0 (CON), 2.5, 5, 7.5, and 10 mM of CRE. The absorbance rate was measured at 0, 24, 48, 72, and 96 h of incubation. Cells for gene expression were plated on 6-well plates at a density of 1 × 105 in 10% FBS/DMEM. Following 24 h of adhesion, SC were incubated with 5 and 7.5mM CRE for 48 h. After which, cells were harvested after 48 h for Pax3, Pax7, and Myf5 mRNA gene expression analysis. To identify the effects of CRE during myogenic differentiation, SCs were induced myogenic differentiation. Upon reaching approximately 90% confluency, the growth medium was replaced by differentiation media (2% horse serum/ DMEM) containing 0 (CON), 5, and 7.5 mM CRE. A two-way ANOVA and Tukey's HSD test were conducted regarding cell proliferation. A one-way ANOVA and Tukey's HSD test were performed for gene expression. Interaction of treatment against time was noted (P < 0.01) in Con, 2.5, 5, 7.5, and 10 mM CRE. Cell proliferation rate was influenced by CRE treatment (P < 0.01). At 72 h of incubation, all CRE treatments increased cell proliferation rate compared with Con (P < 0.05). At 96 h of incubation, cells treated with 2.5, 5, and 7.5 mM of CRE increased proliferation compared with Con (P < 0.05). At 96 h, CRE treatment 2.5, 5, and 7.5 mM increased proliferation rate compared with 10mM CRE treated cells (P < 0.05). No treatment effect was found in the mRNA gene expression of Pax7, Pax3, and Myf5 (P > 0.05). Cells incubated with CRE showed no change in mRNA gene expression of IGF-1 and Myogenin (P > 0.05), and a tendency was noted for S6KB1 increase expression under treatment (P = 0.0643). S6KB1 is a protein kinase that, through mTOR pathway expression, leads to an increase in cell growth, protein synthesis, and cell proliferation. Results suggest that the treatment of BSCs with CRE impacted proliferation, CRE at 5mM vs. 7.5 mM concentrations treatment of differentiated muscle cells led to a trend in altering S6KB1 gene expression.

TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential

Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC “eraser” by mRNA oxidation, abolishes YBX1–HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors.

P-395 Protective effect of metformin on the ovarian reserve of prepubertal mice under cyclophosphamide chemotherapy

Abstract Study question Can metformin reduce the side effects of cyclophosphamide on the ovaries of prepubertal mice treated with cyclophosphamide? Summary answer Yes, metformin, as an inhibitor of mTOR and, by affecting the HIPPO pathway, can exert its protective effect in the chemotherapy mice model. What is known already PI3K/AKT and HIPPO pathways are influential pathways in the process of activation of primordial follicles and proliferation of cell growth, which are affected by various agents and drugs such as cyclophosphamide. One of the side effects of cyclophosphamide is the reduction of the ovarian reserve through abnormal changes in the PI3K/AKT and HIPPO pathways. Metformin is a drug that is used to treat type 2 diabetes and at the same time regulates PI3K/AKT and HIPPO pathways and prohibits the proliferation of cancer cells. Study design, size, duration Controlled experimental study. After metformin and cyclophosphamide dose adjustment, 12 female NMRI 14-day-old mice were randomly divided into four groups: the control group (CONT), metformin group (MET), cyclophosphamide group (CYC) and metformin with cyclophosphamide group (MET-CYC). Participants/materials, setting, methods Mice were treated by intraperitoneal injection of a dose of 150mg/kg of metformin for 11 consecutive days, and/or a dose of 65mg/kg of cyclophosphamide every three days (The third, sixth and ninth days). The mice were sacrificed 24 hours after the last metformin injection or 3 days after the last cyclophosphamide injection. The ovaries were collected for stereological evaluation, and expression of Pten, Mtor, Yap-1, p53, Bcl-2, and Bax genes by qRT-PCR method. Main results and the role of chance The stereological evaluation showed that the ovarian volume and primordial follicle number in the CYC group were decreased compared to the other groups (P < 0.05), and also in the MET-CYC group reduced compared to the CONT and MET groups, but increased significantly compared to the CYC group (P < 0.05). A significantly increased number of growing follicles was observed in the CYC group compared to the other groups (P < 0.05). The molecular analysis showed that the Pten expression in the CYC group was lower than CONT and MET groups (P < 0.05). Mtor expression in the CYC group was significantly increased compared to other groups (P < 0.05). The expression of Yap-1 was significantly decreased in the MET group compared to other groups (P < 0.05), and was lower in the MET-CYC than in the CYC group (P < 0.05). The of P53 expression in the MET-CYC group was higher than CONT and MET groups (P < 0.05), and was increased in the CYC compared to the CONT group (P < 0.05). Bcl-2 expression was higher in CONT and MET groups than in MET-CYC and CYC groups (P < 0.05). The expression of Bax in the CYC group was significantly increased compared to CONT and MET groups (P < 0.05). Limitations, reasons for caution Due to ethical issues in less use of mice, dose of metformin was obtained according to the articles used in adult mice and also by using the human to animal dose conversion formula. Wider implications of the findings It can be concluded that metformin during cyclophosphamide treatment can maintains ovarian volume, reserve, and activity in prepubertal mice by regulating PI3K/AKT and HIPPO pathways. Considering the relatively acceptable cost and long-term safety of metformin, it is a promising factor to be used to preserve fertility during chemotherapy. Trial registration number not applicable

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer.

Cancer is one of the diseases that causes a high mortality as it involves unregulated and abnormal cell growth proliferation that can manifest in any body region. One of the typical ovarian cancer symptoms is damage to the female reproductive system. The death rate can be reduced through early detection of the ovarian cancer. Promising probes that can detect ovarian cancer are suitable aptamers. Aptamers, i.e., so-called chemical antibodies, have a strong affinity for the target biomarker and can typically be identified starting from a random library of oligonucleotides. Compared with other probes, ovarian cancer targeting using aptamers has demonstrated superior detection effectiveness. Various aptamers have been selected to detect the ovarian tumor biomarker, vascular endothelial growth factor (VEGF). The present review highlights the development of particular aptamers that target VEGF and detect ovarian cancer at its earliest stages. The therapeutic efficacy of aptamers in ovarian cancer treatment is also discussed.

BLU-222, an oral, potent, and selective CDK2 inhibitor, in patients with advanced solid tumors: Phase 1 monotherapy dose escalation.

3095 Background: Cell growth regulation and proliferation is dependent on cyclins and CDKs. Cyclin E1 ( CCNE1) is a cell cycle regulator that activates CDK2. A broad range of aggressive cancers overexpress cyclin E and/or harbor CCNE1 gene amplifications. Inhibition or loss of CDK2 impairs the growth of CCNE1-amplified cell lines and cyclin E overexpression represents one of several CDK4/6 inhibitor resistance mechanisms, including in hormone receptor–positive/human epidermal growth factor receptor-2–negative (HR+/HER2−) breast cancer, making CDK2 inhibition a promising novel therapeutic approach. BLU-222 is an investigational, oral, potent, and selective CDK2 inhibitor in early clinical development with best-in-class potential. Methods: VELA (NCT05252416) is an international, open-label, phase 1/2 study evaluating the safety, PK, pharmacodynamics, and efficacy of BLU-222. In monotherapy dose-escalation, adult patients (pts) enrolled regardless of CCNE1 status, but CCNE1 amplification or progression after a CDK4/6 inhibitor were of specific interest. Pts with ECOG PS 0–2 and confirmed nonresectable tumors who had progressed following standard of care for advanced relapsed/recurrent disease were enrolled. BLU-222 was administered BID in continuous 28-day cycles, with dose escalation employing a Bayesian Optimal Interval design to identify the maximum tolerated dose. Blood samples were collected for PK and circulating biomarker analysis. Results: By Jan 29, 2023, 27 pts were enrolled in 6 escalating BID dose cohorts and included in the safety population. Median age was 64 y (range, 29–85); 85% were female. The most frequent cancer types were breast (44%, 12/27), endometrial (15%, 4/27), ovarian (11%, 3/27), and prostate (11%, 3/27). No pts discontinued treatment due to AEs. The most common (≥15%) AEs (all-cause AE; treatment-related AE) were nausea (33%; 26%), vomiting (22%; 11%), anemia (22%; 19%), diarrhea (22%; 22%), and fatigue (18%; 15%). Transient visual AEs (including blurred vision, photophobia, vision change) were seen in 5 pts (19%). These visual symptoms were mild except in 1 pt with Grade (Gr) 3 blurred vision/photophobia; all had fully resolved by/after the data cut-off. There were 2 dose limiting toxicities reported at the 2 highest dose levels: nausea (Gr 3; n=1) and blurred vision/photophobia (Gr 3; n=1). Translational pharmacodynamic data has shown early evidence of pathway modulation. One partial response was seen in a pt with HR+/HER2− metastatic breast cancer previously treated with 5 lines of therapy, including palbociclib, abemaciclib, and capecitabine. Conclusions: As of the cutoff date, BLU-222 monotherapy was generally well tolerated in pts at the BID doses tested. Dose escalation is ongoing to determine the recommended phase 2 dose. Preliminary evidence of cell cycle pathway modulation and clinical activity have been observed. Clinical trial information: NCT05252416 .

Renato Baserga, MD: In Memoriam (1925–2023)

We are saddened by the passing of Renato Baserga, who died on March 5, 2023, several days before his ninety-eighth birthday. Renato's contributions to defining the biology and pathology of the cell cycle and growth control are highly significant and far-reaching. His impact on the understanding of physiological regulation of cell division and cancer-compromised mechanisms that govern proliferation was enormous and mechanistically, as well as clinically, significant.Renato received an MD degree and completed a pathology residency at the University of Milan. He then completed a second residency in oncology and pathology at the Chicago Medical School and graduate training in biochemistry at Northwestern University in Chicago. His early research addressed tumor initiation, progression, and metastasis in animal models, providing important insights into hormonal control of tumorigenesis, including the action of glucocorticoids on tumor growth. As a faculty member at Northwestern University, Renato pioneered the development of autoradiography and radiolabeling approaches to investigate growth control and metabolic regulation in cancer cells. These approaches were instrumental for the development of molecular pathology as a strategy to mechanistically investigate cancer, and they provided a foundation for the evolution of molecular diagnostics.In 1965, Renato moved to Philadelphia. At the Fels Research Institute, Temple University School of Medicine, and at the Thomas Jefferson Kimmel Cancer Center, he developed cancer research programs that provided transformative advances in defining the molecular parameters of cell cycle control in in vivo animal models, as well as in highly informative cell systems. Beyond identification and characterization of regulatory pathways that mediate proliferation, Renato’s work elucidated the relationships between the cell cycle and growth control, proliferation and differentiation, and cell structure and gene expression.In addition to the enormous contributions of his laboratory discoveries that advanced the understanding of cancer biology and pathology, Renato was committed to disseminating research findings. As an associate editor for Cancer Research (1990–2000), he advocated for maximizing effective communication, emphasizing accessibility to the broad biomedical community.While he was devoted to his research, Renato's priority was his family. He was immensely proud of his two daughters, Janice (1959–2016), who was a veterinarian, and Susan, who is an internationally recognized leader in RNA biology and pathology. Renato's wife, Beverly, was his treasured and dedicated partner who meant more to him than words can describe.Renato had a contagious passion for discovery. He was an exceptional mentor and role model for his students. By example, he conveyed the power of innovative thinking as the basis for rigorous and systematic investigation. Renato leaves behind a legacy of insights into aberrant regulatory mechanisms that mediate cancer initiation and progression. In addition, he provided valuable guidance to research scientists and clinical investigators who will continue exploring cancer-compromised regulatory mechanisms to further expand our understanding of cancer biology and pathology.

Melt electrowriting-printed peritoneal scaffold prevents peritoneal adhesion and facilitates peritoneal repair.

Peritoneal adhesion is a critical issue after abdominal surgery. Cell-based methods for preventing peritoneal adhesion have not yet been fully investigated. Here, we constructed a highly biomimetic peritoneal scaffold by seeding mesothelial cells, the natural physiological barrier of the peritoneum, onto a melt electrowriting-printed scaffold. The scaffolds with the microfibers crossed at different angles (30°, 60°, and 90°) were screened based on mesothelial cell proliferation and orientation. Thirty degrees were more suitable for improving proliferation of mesothelial cells and cell growth in a single direction; therefore, the 30° peritoneal scaffold could better mimic the physiological structure of native peritoneum. Mechanistically, such a peritoneal scaffold was able to act as a barrier to prevent peritoneal resident macrophages from migrating to the site of the peritoneal lesion. In vivo mesothelial cell tracking using lentivirus technology confirmed that the peritoneal scaffold, compared to the scaffold without mesothelial cells, could prevent peritoneal adhesion and was directly involved in the repair of injured peritoneum. This study suggests that the peritoneal scaffolds can potentially prevent peritoneal adhesion, offering a new approach for clinical treatment.

Serum starvation-based method of ovarian cancer cell dormancy induction and termination in vitro.

Awakening and growth reinitiation by dormant cells may contribute to epithelial ovarian cancer (EOC) relapse. The links between these phenomena are loose because of the limited stock of compelling models of EOC dormancy. Here, we show a simple and convenient dormancy research protocol based on serum starvation. This study was conducted on established EOC cell lines A2780, OVCAR-3, and SKOV-3, as well as on primary EOC cells. Cell growth arrest and proliferation were monitored by assessing the Ki67 antigen, PKH26 fluorescence, and cell cycle distribution. In addition, cells were tested for ERK1/2/p38 MAPK activity ratio, apoptosis, and senescence. The study showed that 72-h serum starvation induces G0/G1 growth arrest of a significant fraction of cells, accompanied by reduced Ki67 and ERK1/2/p38 MAPK activity ratio, without signs of apoptosis or cellular senescence. Moreover, providing cells with 72 h of a medium enriched in 5% serum allows the culture to regain its proliferative potential. At the same time, we attempted to induce and terminate dormancy with Mitomycin C addition and withdrawal, which were unsuccessful. In conclusion, serum starvation is a convenient way to reliably induce dormancy in EOC cells, allowing them to be efficiently awakened for further mechanistic research in vitro.

Regulation of uncontrolled cell growth (cancer) by curcumin and piperine- A Review

Cancer is a clinical condition of uncontrolled growth of cells. Today one in six people have been suffering from this life threatening disease. It may be benign (localized) or malignant (spread). Besides the common treatment therapies like surgery, chemotherapy and radiotherapy naturally occurring spices like curcumin, found in turmeric(Curcuma longa) and piperine obtained from black peeper (Piper nigrum L) are getting importance for regulation of cancer proliferation. Curcumin and piperine both have the properties to regulate several intracellular signaling pathways acting as antioxidant and antiproliferative agent. According to literature glucuronidation of curcumin leads to formation of other compound that makes the curcumin unavailable and tend to be excreted in feces. On the other hand, piperine increases bioavailability of curcumin by inhibiting glucuronidation of curcumin in the liver and small intestine. So, using both spices together in food and beverages daily can increase the bioavailability of curcumin that could be blessings for cancer patients. In this paper an initiative has been made to illustrate the functions of both curcumin and piperine in inhibition of cell growth proliferation. The knowledge of this paper may be helpful in bio-medical applications and in formulation of new drug development therapy.

Long-term preservation at low temperature of Escherichia coli cells embedded in egg white glass formed by slow drying at room temperature

Sterile homogeneous egg white (EW) is obtained through a three-step process, high-speed homogenization, centrifugation, and ultraviolet radiation. After incorporating 1.056 × 1010 CFU/g of Escherichia coli, the EW mixture was dehydrated by slow drying to form a brittle, water-soluble, and transparent bacteria-embedded egg white glass (BE-EWG). The BE-EWG stored at −20 °C for 4 months maintains almost all the cell growth functions and proliferation activities of the labeled E. coli, and most of the cell functions and 60 % of the proliferation activities are maintained for up to one year. The BE-EWG exhibits a porous hydrogel membrane structure after heat treatment, and many E. coli cells are accommodated in a grid with a pore size of 2–10 mm. The loss of bacteria-carrying viability after storage at room temperature may be related to the Maillard reaction between protein and glucose in EW, which results in the structural changes caused by protein cross-linking, darkened color and water insolubility of the BE-EWG. Therefore, the method of embedding E. coli cells in EWG as solid form at room temperature to avoid ice crystal formation during cryopreservation is more beneficial for storage, packaging and shipping at −20 °C.

Enhanced Anti-cancer Potency Using a Combination of Oleanolic Acid and Maslinic Acid to Control Treatment Resistance in Breast Cancer.

The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/ mTOR) pathway is a complex intracellular metabolic pathway that leads to cell growth and tumor proliferation and plays a key role in drug resistance in breast cancer. Therefore, the anti-cancer effects of oleanolic acid (OA), maslinic acid (MA), and their combination were investigated to improve the performance of the treatment strategy. We investigated the effect of OA and MA on cell viability using the WST-1 method. The synergistic effect of the combination was analyzed by isobologram analysis. In addition, the effects of the two compounds, individually and in combination, on apoptosis, autophagy, and the cell cycle were investigated in MCF7 cells. In addition, changes in the expression of PI3K/AKT/mTOR genes involved in apoptosis, cell cycle and metabolism were determined by quantitative RT-PCR. MA, OA, and a combination of both caused G0/G1 arrest. Apoptosis also increased in all treated groups. The autophagosomal LC3-II formation was induced 1.74-fold in the MA-treated group and 3.25-fold in the MA-OA-treated group. The combination treatment resulted in increased expression of genes such as GSK3B, PTEN, CDKN1B and FOXO3 and decreased expression of IGF1, PRKCB and AKT3 genes. The results showed that the combination of these two substances showed the highest synergistic effect at the lowest dose and using MA-OA caused cancer cells to undergo apoptosis. The use of combination drugs may reduce the resistance of cancer cells to treatment.