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BRCA1/2 proteins function in homologous recombination (HR)-mediated DNA repair and cooperate with Fanconi anemia (FA) proteins to maintain genomic integrity through replication fork stabilization. Loss of BRCA1/2 proteins results in DNA repair deficiency and replicative stress, leading to genomic instability and enhanced sensitivity to DNA-damaging agents. Recent studies have shown that BRCA1/2-deficient tumors upregulate Polθ-mediated alternative end-joining (alt-EJ) repair as a survival mechanism. Whether other mechanisms maintain genomic integrity upon loss of BRCA1/2 proteins is currently unknown. Here we show that BRCA1/2-deficient tumors also upregulate FANCD2 activity. FANCD2 is required for fork protection and fork restart in BRCA1/2-deficient tumors. Moreover, FANCD2 promotes Polθ recruitment at sites of damage and alt-EJ repair. Finally, loss of FANCD2 in BRCA1/2-deficient tumors enhances cell death. These results reveal a synthetic lethal relationship between FANCD2 and BRCA1/2, and they identify FANCD2 as a central player orchestrating DNA repair pathway choice at the replication fork.

Chromatin integrity is key for cell homeostasis and for preventing pathological development. Alterations in core chromatin components, histone proteins, recently came into the spotlight through the discovery of their driving role in cancer. Building on these findings, in this review, we discuss how histone variants and their associated chaperones safeguard genome stability and protect against tumorigenesis. Accumulating evidence supports the contribution of histone variants and their chaperones to the maintenance of chromosomal integrity and to various steps of the DNA damage response, including damaged chromatin dynamics, DNA damage repair, and damage-dependent transcription regulation. We present our current knowledge on these topics and review recent advances in deciphering how alterations in histone variant sequence, expression, and deposition into chromatin fuel oncogenic transformation by impacting cell proliferation and cell fate transitions. We also highlight open questions and upcoming challenges in this rapidly growing field.

Introduction: The main purpose of reconstructive surgery (RS) is to restore the integrity of soft tissues damaged by trauma, surgery, congenital deformity, burns, or infection. Microsurgical techniques consist of harvesting tissues that are separated from the vascular sources of the donor site and anastomosed to the vessels of the recipient site. In these procedures, there are some preoperative modifiable factors that have the potential to influence the outcome of the flap transfer and its anastomosis. The management of anemia, which is always present in the postoperative period and plays a decisive role in the implantation of the flap, covers significant importance, and is associated with clinical and laboratory settings of chronic inflammation. Methods: Chronic inflammatory anemia (ACD) is a constant condition in patients who have undergone RS and correlates with the perfusion of the free flap. The aim of this treatment protocol is to reduce the transfusion rate by maintaining both a good organ perfusion and correction of the patient’s anemic state. From January 2017 to September 2019, we studied 16 patients (16 males, mean age 38 years) who underwent microsurgical procedures for RS. Their hemoglobin (Hb) levels, corpuscular indexes, transferrin saturation (TSAT) ferritin concentrations and creatinine clearance were measured the first day after surgery (T0), after the first week (T1), and after five weeks (T2). At T0, all the patients showed low hemoglobin levels (average 7.4 g/dL, STD 0.71 range 6.2–7.4 g dL−1), with an MCV of 72, MCH of 28, MCHC of 33, RDW of 16, serum iron of 35, ferritin of 28, Ret% of 1.36, TRF of 277, creatinine clearance of 119 and high ferritin levels (range 320–560 ng mL−1) with TSAT less than 20%. All the patients were assessed for their clinical status, medical history and comorbidities before the beginning of the therapy. Results: A collaboration between the two departments (Department of Transfusion Medicine and Department of Reconstructive Surgery) resulted in the application of a therapeutic protocol with erythropoietic stimulating agents (ESAs) (Binocrit 6000 UI/week) and intravenous iron every other day, starting the second day after surgery. Thirteen patients received ESAs and FCM (ferric carboxymaltose, 500–1000 mg per session), three patients received ESAs and iron gluconate (one vial every other day). No patients received blood transfusions. No side effects were observed, and most importantly, no limb or flap rejection occurred. Conclusions: Preliminary data from our protocol show an optimal therapeutic response, notwithstanding the very limited scientific literature and data available in this specific surgical field. The enrollment of further patients will allow us to validate this therapeutic protocol with statistically sound data.

This article provides additional data on the application of early coagulation support protocol in the management of major trauma patients. Data come from a retrospective analysis reported in the article “Early coagulation support protocol: a valid approach in real-life management of major trauma patients. Results from two Italian centres” [1]. Data contain information about the relationship between differences in resource use and mortality outcomes, and patient demographic and clinical features at presentation. Furthermore, a comparison between resource consumption, the probability of multiple transfusions and the mortality outcomes among propensity-score matched patients is reported. Keywords: Blood coagulation, Critical care, Fibrinogen, Haemorrhage, Italy, Propensity score, Sensitivity analysis, Trauma centres