Enhancing Anti-PD-1 Immunotherapy by Targeting MDSCs via Hepatic Arterial Infusion in Breast Cancer Liver Metastases.

Background: Surgery, chemotherapy, and radiation often have limited utility for advanced metastatic disease in the liver, and despite its promising activity in select cancers, PD-1 blockade therapy similarly has minimal benefit in this setting. Curaxin, CBL0137, is an experimental anti-cancer drug that disrupts the binding of DNA to histones, destabilizes chromatin, and induces Z-DNA formation which may stimulate anti-tumor immune responses.

Methods: Murine cell lines of colon (CT26) and breast (4T1) cancer were interrogated for survival and CBL0137-associated DNA changes in vitro.

Anticancer Plant Secondary Metabolites Induce Linker Histone Depletion from Chromatin.

Background: Many plant secondary metabolites (PSMs) were shown to intercalate into DNA helix or interact with DNA grooves. This may influence histone-DNA interactions changeing chromatin structure and genome functioning.

Methods: Nucleosome stability and linker histone H1.

Comparison of cell response to chromatin and DNA damage.

DNA-targeting drugs are widely used for anti-cancer treatment. Many of these drugs cause different types of DNA damage, i.e.

Comparison of cell response to chromatin and DNA damage.

DNA-targeting drugs may damage DNA or chromatin. Many anti-cancer drugs damage both, making it difficult to understand their mechanisms of action. Using molecules causing DNA breaks without altering nucleosome structure (bleomycin) or destabilizing nucleosomes without damaging DNA (curaxin), we investigated the consequences of DNA or chromatin damage in normal and tumor cells.

FACT maintains nucleosomes during transcription and stem cell viability in adult mice.

Preservation of nucleosomes during replication has been extensively studied, while the maintenance of nucleosomes during transcription has gotten less attention. The histone chaperone FACT has a role in transcription elongation, although whether it disassembles or assembles nucleosomes during this process is unclear. To elucidate the function of FACT in mammals, we deleted the Ssrp1 subunit of FACT in adult mice.

Nutritional Complications After Laparoscopic Roux-en-Y Gastric Bypass and One-Anastomosis Gastric Bypass: A Comparative Systematic Review and Meta-Analysis.

A systematic review and meta-analysis were carried out involving studies that compared the nutritional complications of Roux-en-Y gastric bypass (RYGB) and one-anastomosis gastric bypass (OAGB); these included the incidence of malnutrition as well as deficiencies of other nutritional elements, such as total protein, albumin, calcium and iron. A comprehensive search strategy was implemented in PubMed, Embase, and the Cochrane Library. Effect sizes included the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs), as well as mean differences (MDs) and 95% CIs of the percentage total weight loss (%TWL) and excess weight loss percentage (%EWL).

The Impact of Drain and Reinforcement on the Outcomes of Bariatric Surgery: A Prospective Study.

Purpose We aimed to investigate the impact of reinforcement and abdominal drains on the outcome of laparoscopic sleeve gastrectomy (LSG). Methods The present study was a prospective study that included obese patients scheduled to undergo LSG. Patients were assigned to receive drain, reinforcement, or both according to the surgeon's preference and followed up for one month after surgery.

The benefit of adding lidocaine to ketamine during rapid sequence endotracheal intubation in patients with septic shock: A randomised controlled trial.

Background: Patients with septic shock commonly require endotracheal intubation under general anaesthesia in the operating theatre, the emergency department, and the intensive care unit. Hypotension is a serious complication after induction of general anaesthesia, especially in patients with circulatory failure. No randomised controlled trials had previously investigated protocols for induction of anaesthesia in septic shock patients.

[Resolution of the Council of Experts «Bioregulatory drugs in the complex treatment of common ENT diseases»].

Within the framework of the III All-Russian scientific and practical conference of otorhinolaryngologists, audiologists, somnologists and maxillofacial surgeons with international participation, a meeting of experts in the field of ENT diseases was held with the support of Heel RUS LLC, October 17-18, 2019, Kazan.

Modified-ramped position: a new position for intubation of obese females: a randomized controlled pilot study.

Background: Endotracheal intubation requires optimum position of the head and neck. In obese females, the usual ramped position might not provide adequate intubating conditions. We hypothesized that a new position, termed modified-ramped position, during induction of anesthesia would facilitate endotracheal intubation through bringing the breasts away from the laryngoscope and would also improve the laryngeal visualization.

Histone chaperone FACT is essential to overcome replication stress in mammalian cells.

The histone chaperone FACT is upregulated during mammary tumorigenesis and necessary for the viability and growth of breast tumor cells. We established that only proliferating tumor cells are sensitive to FACT knockdown, suggesting that FACT functions during DNA replication in tumor cells but not in normal cells. We hypothesized that the basal level of replication stress defines the FACT dependence of cells.

Prevention of Chromatin Destabilization by FACT Is Crucial for Malignant Transformation.

Histone chaperone FACT is commonly expressed and essential for the viability of transformed but not normal cells, and its expression levels correlate with poor prognosis in patients with cancer. FACT binds several components of nucleosomes and has been viewed as a factor destabilizing nucleosomes to facilitate RNA polymerase passage. To connect FACT's role in transcription with the viability of tumor cells, we analyzed genome-wide FACT binding to chromatin in conjunction with transcription in mouse and human cells with different degrees of FACT dependence.

Accuracy and trending of non-invasive oscillometric blood pressure monitoring at the wrist in obese patients.

Background: In obese patients, non-invasive blood pressure monitoring in the arm is difficult due to the arm size and morphology. We compared the non-invasive oscillometric wrist blood pressure measurement with the arm and forearm in obese patients monitored with invasive radial blood pressure (reference standard).

Methods: This prospective observational study included adult obese patients scheduled for bariatric surgery.

Prevention of Colorectal Carcinogenesis by DNA-Binding Small-Molecule Curaxin CBL0137 Involves Suppression of Wnt Signaling.

Chemoprevention is considered a valid approach to reduce the incidence of colorectal cancer, one of the most common malignancies worldwide. Here, we investigated the tumor-preventive activity of curaxin CBL0137. This compound represents a new class of nonmutagenic DNA-binding small molecules that alter chromatin stability and inhibit the function of the histone chaperone FACT.

The anti-cancer drugs curaxins target spatial genome organization.

Recently we characterized a class of anti-cancer agents (curaxins) that disturbs DNA/histone interactions within nucleosomes. Here, using a combination of genomic and in vitro approaches, we demonstrate that curaxins strongly affect spatial genome organization and compromise enhancer-promoter communication, which is necessary for the expression of several oncogenes, including MYC. We further show that curaxins selectively inhibit enhancer-regulated transcription of chromatinized templates in cell-free conditions.

Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins.

Human FACT (facilitates chromatin transcription) is a multifunctional protein complex that has histone chaperone activity and facilitates nucleosome survival and transcription through chromatin. Anticancer drugs curaxins induce FACT trapping on chromatin of cancer cells (c-trapping), but the mechanism of c-trapping is not fully understood. Here, we show that in cancer cells, FACT is highly enriched within the bodies of actively transcribed genes.

Uncovering the fine print of the CreERT2-LoxP system while generating a conditional knockout mouse model of Ssrp1 gene.

FAcilitates Chromatin Transcription (FACT) is a complex of SSRP1 and SPT16 that is involved in chromatin remodeling during transcription, replication, and DNA repair. FACT has been mostly studied in cell-free or single cell model systems because general FACT knockout (KO) is embryonically lethal (E3.5).

TGF-β signaling promotes tumor vasculature by enhancing the pericyte-endothelium association.

Background: The breast cancer microenvironment promotes tumor vascularization through the complex interactions involving tumor-associated fibroblasts (TAFs). Emerging data indicate that TAFs increase production and signaling by TGF-β cytokines, while the role of TGF-β signaling in the regulation of tumor blood vessels is not fully understood. The current study presents evidence that TAFs enhance the organization of tumor blood capillaries, and TGF-β signaling plays an important role in this response.

TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells.

Cellular responses to the loss of genomic stability are well-established, while how mammalian cells respond to chromatin destabilization is largely unknown. We previously found that DNA demethylation on p53-deficient background leads to transcription of repetitive heterochromatin elements, followed by an interferon response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, an anticancer small molecule, destabilizing nucleosomes via disruption of histone/DNA interactions, also induces TRAIN.

Role of Chromatin Damage and Chromatin Trapping of FACT in Mediating the Anticancer Cytotoxicity of DNA-Binding Small-Molecule Drugs.

Precisely how DNA-targeting chemotherapeutic drugs trigger cancer cell death remains unclear, as it is difficult to separate direct DNA damage from other effects in cells. Recent work on curaxins, a class of small-molecule drugs with broad anticancer activity, shows that they interfere with histone-DNA interactions and destabilize nucleosomes without causing detectable DNA damage. Chromatin damage caused by curaxins is sensed by the histone chaperone FACT, which binds unfolded nucleosomes becoming trapped in chromatin.

Tumor p38MAPK signaling enhances breast carcinoma vascularization and growth by promoting expression and deposition of pro-tumorigenic factors.

The breast carcinoma microenvironment strikingly influences cancer progression and response to therapy. Various cell types in the carcinoma microenvironment show significant activity of p38 mitogen-activated protein kinase (MAPK), although the role of p38MAPK in breast cancer progression is still poorly understood. The present study examined the contribution of tumor p38MAPK to breast carcinoma microenvironment and metastatic capacity.

Tumor-fibroblast interactions stimulate tumor vascularization by enhancing cytokine-driven production of MMP9 by tumor cells.

Advance-stage breast carcinomas include significant amounts of fibroblasts and infiltrating immune cells which have been implicated in tumor growth, recurrence, and response to therapy. The present study investigated the contribution of fibroblasts to tumor growth using direct tumor-fibroblast co-cultures and tumor xenograft models. Our findings revealed that fibroblasts enhance breast carcinoma growth by promoting the tumor vasculature via the MMP9-dependent mechanism.

Level of FACT defines the transcriptional landscape and aggressive phenotype of breast cancer cells.

Although breast cancer (BrCa) may be detected at an early stage, there is a shortage of markers that predict tumor aggressiveness and a lack of targeted therapies. Histone chaperone FACT, expressed in a limited number of normal cells, is overexpressed in different types of cancer, including BrCa. Recently, we found that FACT expression in BrCa correlates with markers of aggressive BrCa, which prompted us to explore the consequences of FACT inhibition in BrCa cells with varying levels of FACT.

FACT is a sensor of DNA torsional stress in eukaryotic cells.

Transitions of B-DNA to alternative DNA structures (ADS) can be triggered by negative torsional strain, which occurs during replication and transcription, and may lead to genomic instability. However, how ADS are recognized in cells is unclear. We found that the binding of candidate anticancer drug, curaxin, to cellular DNA results in uncoiling of nucleosomal DNA, accumulation of negative supercoiling and conversion of multiple regions of genomic DNA into left-handed Z-form.

Anticancer drug candidate CBL0137, which inhibits histone chaperone FACT, is efficacious in preclinical orthotopic models of temozolomide-responsive and -resistant glioblastoma.

Background: The survival rate for patients with glioblastoma (GBM) remains dismal. New therapies targeting molecular pathways dysregulated in GBM are needed. One such clinical-stage drug candidate, CBL0137, is a curaxin, small molecules which simultaneously downregulate nuclear factor-kappaB (NF-ĸB) and activate p53 by inactivating the chromatin remodeling complex, Facilitates Chromatin Transcription (FACT).