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The posterior interosseous flap (PIOF), as fasciocutaneous flap, represents an interesting option in reconstructive surgery of the upper limb. The PIOF allows coverage of losses of substance of the dorsal side of the hand and, with technical modifications, up to the proximal interphalangeal (PIP) joint without any need of microsurgical technique or the sacrifice of the main vascular axes for the hand. Its dimensions can reach up to 22 cm x12 cm and have excellent versatility since it can incorporate vascularized bone grafts and tendon grafts for complex substance losses. Despite the above-mentioned advantages, among the factors that limit its diffusion, indeed, there is the complex dissection technique originally described. Several authors also report a variable incidence of venous congestion, attributing it to the reverse flow vascularity of the flap. However, in the hands of experienced surgeons, this flap has a negligible incidence of complications. For these reasons, the authors performed a systematic review of the literature to organize the various technical updates over the years to extend the indications of the PIOF and reduce the incidence of complications, thus providing a valuable tool for reconstructive surgeons.

OBJECTIVE: The purpose of this article is to describe a protocol to examine the feasibility of combining podiatric orthotic treatment with multimodal chiropractic treatment to treat chronic low back pain (CLBP) in those with a functional short leg on the same side as a unilateral pronated foot. METHODS: This is a protocol for a multicenter feasibility 2-arm parallel randomized controlled trial. One hundred and thirty-two adults with CLBP and a functional short leg on the same side as a unilateral pronated foot are to be recruited in Melbourne, Australia, and Madrid and Seville, Spain. Forty-four participants at each site are to be randomized to multimodal chiropractic treatment including spinal manipulation or to multimodal chiropractic treatment also involving spinal manipulation, together with podiatric custom-made orthoses. Chiropractic visits are to comprise 12 treatments over 4 weeks. Outcome measures will be recruitment, compliance, costs, CLBP-related disability, and perceived low back pain. RESULTS: Feasibility results will be reported in text format and the clinical data reported using descriptive statistics focusing on any clinically significant results. CONCLUSION: This protocol describes a feasibility study for assessing the combination of podiatric orthotic treatment with multimodal chiropractic treatment to treat CLBP in those with a functional short leg on the same side as a unilateral pronated foot.

Objective Poly ADP ribose polymerase inhibitors (PARPi) are most effective in BRCA1/2 mutated ovarian tumors. Better treatments are needed for homologous recombination HR-proficient cancer, including CCNE1 amplified subtypes. We have shown that histone deacetylase inhibitors (HDACi) sensitize HR-proficient ovarian cancer to PARPi. In this study, we provide complementary preclinical data for an investigator-initiated phase 1/2 clinical trial of the combination of olaparib and entinostat in recurrent, HR-proficient ovarian cancer. Methods We assessed the in vitro effects of the combination of olaparib and entinostat in SKOV-3, OVCAR-3 and primary cells derived from CCNE1 amplified high grade serous ovarian cancer (HGSOC) patients. We then tested the combination in a SKOV-3 xenograft model and in a patient-derived xenograft (PDX) model. Results Entinostat potentiates the effect of olaparib in reducing cell viability and clonogenicity of HR-proficient ovarian cancer cells. The combination reduces peritoneal metastases in a SKOV-3 xenograft model and prolongs survival in a CCNE1 amplified HR-proficient PDX model. Entinostat also enhances olaparib-induced DNA damage. Further, entinostat decreases BRCA1, a key HR repair protein, associated with decreased Ki-67, a proliferation marker, and increased cleaved PARP, a marker of apoptosis. Finally, entinostat perturbs replication fork progression, which increases genome instability. Conclusion Entinostat inhibits HR repair by reducing BRCA1 expression and stalling replication fork progression, leading to irreparable DNA damage and ultimate cell death. This work provides preclinical support for the clinical trial of the combination of olaparib and entinostat in HR-proficient ovarian cancer and suggests potential benefit even for CCNE1 amplified subtypes.

Accurate DNA replication is constantly threatened by DNA lesions arising from endogenous and exogenous sources. Specialized DNA replication stress response pathways ensure replication fork progression in the presence of DNA lesions with minimal delay in fork elongation. These pathways broadly include translesion DNA synthesis, template switching, and replication fork repriming. Here, we discuss recent advances toward our understanding of the mechanisms that regulate the fine-tuned balance between these different replication stress response pathways. We also discuss the molecular pathways required to fill single-stranded DNA gaps that accumulate throughout the genome after repriming, and the biological consequences of using repriming instead of other DNA damage tolerance pathways on genome integrity and cell fitness.

Cancers with deficiencies in homologous recombination-mediated DNA repair (HRR) demonstrate improved clinical outcomes and increased survival. Approximately 50% of high-grade serous ovarian cancers (HGSOC) exhibit homologous recombination deficiency (HRD). HRD can be caused by germline or somatic mutations of genes involved in the HR pathway. Given platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARPis) are used in HGSOC, double-strand breaks (DSBs) are common. Unrepaired DSBs are toxic to cells as genomic instability ensues and cells eventually die. Thus, tumor cells with DSBs utilize the high-fidelity HRR as one of the central pathways for repair. In tumors that have HRD, an alternate pathway such as non-homologous end-joining (NHEJ) is used and leads to error-prone repair. To date, methods for clinical detection of homologous recombination deficiency (HRD) are limited to genomic changes of HRR genes and genomic mutation patterns resulting from HRD genes involved in HR-mediated DNA repair. However, these tests detect genomic scars that might not always correlate well with PARP inhibitor or platinum sensitivity in the current state. Therefore, a functional HRD assay should be able to more accurately predict tumor response in real-time. RAD51 foci formation has been used as a functional assay to define HRD and closely correlates with chemotherapy and PARPi sensitivity. The inability to form RAD51 foci is a common feature of HRD. DNA damage can also cause transient slowing or stalling of replication forks defined as replication stress. Replication fork stalling can lead to fork degradation and decreased cell viability if forks do not resume DNA synthesis. Fork degradation has been found to lead to chemosensitivity in BRCA-deficient tumors. To determine this fork degradation phenotype, replication fork/DNA fiber assays are utilized. This review will highlight functional assays for HRD in the context of translating these to real-time clinical assays.

Summary Background Dermoscopy improves sensitivity and specificity and helps in the early detection of melanoma and nonmelanoma skin cancers (NMSC). Because of the multidisciplinary approach to melanoma, plastic surgeons may be required to perform dermoscopy evaluation. For this reason, in some university hospitals, plastic surgeons in training might perform these evaluations. To assess the validity of digital dermoscopy conducted by plastic surgery registrars, the authors collected the diagnoses of excised lesions from a dermoscopy outpatient clinic, comparing results with literature. Methods A total of 1094 consecutive dermoscopy evaluations performed at Padova University Hospital between 2015 and 2018 were included in the study. All examinations were carried out by 3 plastic surgery registrars who received comparable training on dermoscopy. Excised lesions were classified according to pathological reports. Results Four hundred sixty-six lesions were excised, and of them, 224 (48%) were considered pathological or atypical lesions: 34 melanomas (15%), 83 dysplastic or uncertain significance nevi (37%), and 107 NMSC and their precursors (48%). Considering only the 347 pigmented lesions, 34% were malignant or dysplastic lesions. The number needed to treat (NNT) was 10. The nevi-to-melanoma ratio (NMR) was 8, and the malignant melanoma-to-melanoma in situ ratio (MM:MMIS ratio) was 0.36. Conclusions This retrospective study tested the performance of specifically trained plastic surgery registrars in the detection of malignant skin lesions. Compared to literature, the analysis reflects a good sensibility for melanoma, especially in early curable stages. Moreover, our study underlines quite a high number of total excisions, which could be explained by the “surgical imprinting” of plastic surgery registrars.

The concept of 'BRCAness' defines the pathogenesis and vulnerability of multiple cancers. The canonical definition of BRCAness is a defect in homologous recombination repair, mimicking BRCA1 or BRCA2 loss. In turn, BRCA-deficient cells utilize error-prone DNA-repair pathways, causing increased genomic instability, which may be responsible for their sensitivity to DNA damaging agents and poly-(ADP)-ribose polymerase inhibitors (PARPis). However, recent work has expanded the mechanistic basis of BRCAness, to include defects in replication fork protection (RFP). Here, we broaden the definition of BRCAness to include RFP and regulatory mechanisms that cause synthetic lethality with PARPis. We highlight these recent discoveries, which include mechanisms of RFP regulation, DNA damage checkpoint proteins, as well as kinases that regulate BRCA1/2 function. Importantly, many of these emerging mechanisms may be targeted for inhibition with small molecule inhibitors, thus inducing BRCAness in a much larger subset of BRCA-proficient tumors, with significant translational potential.

Les patients atteints de sclerodermie peuvent beneficier des avantages de la greffe de graisse, apparue comme un traitement “regenerant” pour les tissus cicatrises. Cette greffe a ete realisee sur 12 patients atteints de fibrose peri-orale dans la sclerodermie, determinant les deficiences fonctionnelles. Ils ont ete suivis jusqu’a douze mois, a l’aide d’un questionnaire postoperatoire pour la performance fonctionnelle subjective et l’evaluation echographique des greffes de graisse. Tous ont rapporte un benefice significatif en douceur, en ouverture buccale et en apparence a un et a trois mois. Un patient a rapporte une regression totale en trois mois. Les autres ont note une regression partielle des benefices entre trois et six mois, avec des resultats stables a un an. Les echographies en serie ont confirme une augmentation de l’epaisseur dans les zones greffees, avec reabsorption dans le temps. Aucune variation dans les mesures des levres n’a ete detectee. La greffe de graisse semble donc etre donc une option pour soulager les patients atteints de sclerodermie systemique presentant une insuffisance peribuccale.

Selective targeting is a crucial property of nanocarriers used for drug delivery in cancer therapy. We generated biotinylated octahedral DNA nanocages functionalized with folic acid through bio-orthogonal conjugation chemistry. Molecular modelling indicated that a distance of about 2.5 nm between folic acid and DNA nanocage avoids steric hindrance with the folate receptor. HeLa cells, a folate receptor positive tumour cell line, internalize folate-DNA nanocages with efficiency greater than 40 times compared to cells not expressing the folate receptors. Functionalized DNA nanocages are highly stable, not cytotoxic and can be efficiently loaded with the chemotherapeutic agent doxorubicin. After entry into cells, doxorubicin-loaded nanoparticles are confined in vesicular structures, indicating that DNA nanocages traffic through the endocytic pathway. Doxorubicin release from loaded DNA cages, facilitated by low pH of endocytic vesicles, induces toxic pathways that, besides selectively killing folate receptor-positive cancer cells, leads to cage degradation avoiding nanoparticles accumulation inside cells.

PRIMPOL repriming allows DNA replication to skip DNA lesions, leading to ssDNA gaps. These gaps must be filled to preserve genome stability. Using a DNA fiber approach to directly monitor gap filling, we studied the post-replicative mechanisms that fill the ssDNA gaps generated in cisplatin-treated cells upon increased PRIMPOL expression or when replication fork reversal is defective because of SMARCAL1 inactivation or PARP inhibition. We found that a mechanism dependent on the E3 ubiquitin ligase RAD18, PCNA monoubiquitination, and the REV1 and POLζ translesion synthesis polymerases promotes gap filling in G2. The E2 conjugating enzyme UBC13, the RAD51 recombinase, and REV1-POLζ are instead responsible for gap filling in S, suggesting that temporally distinct pathways of gap filling operate throughout the cell cycle. Furthermore, we found that BRCA1 and BRCA2 promote gap filling by limiting MRE11 activity and that simultaneously targeting fork reversal and gap filling enhances chemosensitivity in BRCA-deficient cells.

Replication fork reversal is a rapidly emerging and remarkably frequent mechanism of fork stabilization in response to genotoxic insults. Here, we summarize recent findings that uncover key molecular determinants for reversed fork formation and describe how the homologous recombination factors BRCA1, BRCA2, and RAD51 protect these structures from extended nucleolytic degradation.

A novel time dependent version of the Traveling Purchaser Problem is presented.A LP model introducing constrains to represent dynamically changing quantities is defined.An exact method based on a branch-and-cut algorithm exploiting the structure of the problem is described.Experiments over a wide set of instances show the efficacy of the proposed approach. The deterministic Traveling Purchaser Problem looks for a tour visiting a subset of markets in order to satisfy a positive discrete demand for some products at minimum traveling and purchasing costs. In this paper, we assume that the quantities available in the markets for all the products are time-varying decreasing at a constant rate. We propose a compact mixed integer formulation for the problem, and strengthen it with the introduction of connectivity constraints. A new branching strategy and a primal heuristic enforcing the bounding operations have been embedded into a branch-and-cut framework. The branching rule exploits a simple valid inequality and the potential presence of necessary markets. The resulting method outperforms CPLEX 12.6 when used to solve the proposed model. The algorithms have been tested on standard TSPLIB instances, modified to include products and quantities that decrease at different rates of consumption.

A novel stochastic version of the orienteering problem is considered.The problem generalizes the probabilistic TSP.A deterministic equivalent MILP model is derived.A branch-and-cut procedure with special branching rules is developed.Matheuristic procedures are proved to be efficient and effective. The probabilistic orienteering problem (POP) is defined on a directed graph where a cost is associated with each arc and a prize is associated with each node. Moreover, each node will be available for visit only with a certain probability. A server starts from a fixed origin, has a given budget to visit a subset of nodes, and ends at a fixed destination. In a first stage, a node subset has to be selected and a corresponding a priori path has to be determined such that the server can visit all nodes in the subset and reach the destination without exceeding the budget. The list of available nodes in the subset is then revealed. In a second stage, the server follows the a priori path by skipping the absent nodes. The POP consists in determining a first-stage solution that maximizes the expected profit of the second-stage path, where the expected profit is the difference between the expected total prize and the expected total cost.We discuss the relevance of the problem and formulate it as a linear integer stochastic problem. We develop a branch-and-cut approach for the POP and several matheuristic methods, corresponding to different strategies to reduce the search space of the exact method. Extensive computational tests on instances with up to 100 nodes show the effectiveness of the exact method and the efficiency of the matheuristics in finding high quality solutions in a few minutes. Moreover, we provide an extended analysis on a subset of instances to show the value of explicitly modeling the stochastic information in the problem formulation.

Fecal microbiota transplantation (FMT) is the transfer of stool from a healthy donor into the colon of a patient whose disease is a result of an altered microbiome, with the goal of restoring the normal microbiota and thus curing the disease. The most effective and well-studied indication for FMT is recurrent Clostridium difficile infection. At this time, there is insufficient evidence to recommend FMT for other gastrointestinal diseases, but studies are under way. There is also insufficient evidence to recommend FMT for nongastrointestinal diseases at this time. The field is rapidly emerging.

Objectives: More than 80% of women with high grade serous ovarian carcinoma (HGSOC) ultimately develop platinum resistance. There are no FDA approved agents to improve sensitivity to carboplatin. On candidate target is growth arrest-specific 6 (GAS6) which has been associated with prognosis in HGSOC. We hypothesized that GAS6 inhibition with AVB-500 (AVB) sensitizes platinum-resistant cells to platinum chemotherapy by stalling replication forks and increasing replication stress. We also hypothesized that GAS6 expression would predict response to neoadjuvant chemotherapy. Methods: AVB was supplied by Aravive Biologics. Both homologous recombination (HR)-proficient (OVCAR3-TPMES, CAOV3, COV362) and HR-deficient (OVCAR8) cells were used for all experiments. In vitro clonogenic assays were done on chemoresistant ovarian tumor cells treated with carbo±AVB. The effect of carbo + AVB on intraperitoneal tumor burden was evaluated in mouse models. For DNA fiber assays, cells were labeled with the thymidine analog IdU for 20 minutes followed by CldU for 60 minutes and treatment with carbo, cisplatin (cis), or AVB. Immunofluorescent (IF) assays targeting γH2AX for DNA damage, RAD51, BRCA1, and BRCA2 for HR and 53BP1 for non-homologous end joining (NHEJ) were performed. Human HGSOC samples were obtained pre- and post-neoadjuvant chemotherapy. GAS6 expression was measured by tissue immunohistochemistry (IHC) and serum ELISA. Results: Carbo + AVB decreased survival of platinum-resistant cells as measured by clonogenic colonies than carbo alone (p 80%) (n=7) or serum GAS6 concentrations (>25ng/mL) (n=13) were more likely to have a poor response to neoadjuvant chemotherapy than those with low GAS6 (P=0.002). Additionally, high GAS6 concentration was associated with decreased overall survival (24.4 months versus median not reached, P=0.009). Conclusions: Inhibition of the GAS6 pathway with AVB improves sensitivity of platinum-resistant cells to platinum chemotherapy by increasing replication stress and DNA damage and decreasing HR. GAS6 is a potential biomarker predictive of poor response to platinum-based neoadjuvant chemotherapy and might identify patients who would benefit from treatment with AVB.

RAD51 facilitates replication fork reversal and protects reversed forks from nuclease degradation. Although potentially a useful replication stress response mechanism, unregulated fork reversal can cause genome instability. Here we show that RADX, a single-strand DNA binding protein that binds to and destabilizes RAD51 nucleofilaments, can either inhibit or promote fork reversal depending on replication stress levels. RADX inhibits fork reversal at elongating forks, thereby preventing fork slowing and collapse. Paradoxically, in the presence of persistent replication stress, RADX localizes to stalled forks to generate reversed fork structures. Consequently, inactivating RADX prevents fork-reversal-dependent telomere dysfunction in the absence of RTEL1 and blocks nascent strand degradation when fork protection factors are inactivated. Addition of RADX increases SMARCAL1-dependent fork reversal in conditions in which pre-binding RAD51 to a model fork substrate is inhibitory. Thus, RADX directly interacts with RAD51 and single-strand DNA to confine fork reversal to persistently stalled forks.