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Replication fork reversal safeguards genome integrity as a replication stress response. DNA translocases and the RAD51 recombinase catalyze reversal. However, it remains unknown why RAD51 is required and what happens to the replication machinery during reversal. We find that RAD51 uses its strand exchange activity to circumvent the replicative helicase, which remains bound to the stalled fork. RAD51 is not required for fork reversal if the helicase is unloaded. Thus, we propose that RAD51 creates a parental DNA duplex behind the helicase that is used as a substrate by the DNA translocases for branch migration to create a reversed fork structure. Our data explain how fork reversal happens while maintaining the helicase in a position poised to restart DNA synthesis and complete genome duplication.

Background: Triple negative breast cancer (TNBC), defined by negative hormone receptor (HR) status and the lack of HER2 gene amplification, is a significant clinical challenge because of its aggressive clinical course and association with a poor prognosis. Recent studies demonstrated that approximately a third of TNBC has low expression of HER2, so called HER2-low TNBC, which could be targeted by the new generation HER2-directed antibody-drug conjugate (ADC). Trastuzumab deruxtecan (also known as T-Dxd, DS-8201a) is a novel HER2-directed ADC with a topoisomerase 1 inhibitor payload and a tetrapeptide-based cleavable linker, which has been FDA approved for patients with metastatic HER2-positive, or amplified breast cancer. T-Dxd has also shown to improve survival outcomes when compared to physicians’ choice chemotherapy in patients with metastatic HR-negative/HER2-low breast cancer in the Phase 3 DESTINY-Breast04 trial. However, resistance is invariable. We hypothesize that small molecule inhibitors against DNA damage response (DDR) pathways could potentiate the DNA damaging effect of T-Dxd and improve its anti-tumor activity in HER2-low TNBC. Method: We conducted preclinical experiments to assess the anti-tumor activity of T-Dxd and each of the DDR pathway inhibitors, including the ATR inhibitor AZD6738, the ATM inhibitor AZD1390, and the PARP inhibitor olaparib, as well as the Wee 1 inhibitor AZD1775, either alone or in combination, compared to the vehicle treatment, in a panel of HER2-low TNBC PDX models in vivo, as well as mechanistic studies using HER2-low TNBC cell lines in vitro. HER2-low was defined as 1+ or 2+ on HER2 immunohistochemistry. Results: Four HER2-low TNBC PDX models, including WHIM2 (TP53 mutated, basal-like), WHIM6 (TP53 WT, basal-like), WHIM12 (TP53, PIK3CA, and PTEN mutated, claudin-low), and WHIM30 (BRCA1 and TP53 mutated, basal-like), as well as a panel of 4 TNBC cell lines with variable HER2 expression were included in the study. We demonstrated that the addition of DDR pathway inhibitors to T-Dxd led to further tumor shrinkage and delayed tumor progression in HER2-low TNBC PDX models in vivo and induced synergistic anti-tumor effects in vitro. Enhanced DNA damaging effect and apoptosis induction were observed with combination therapies in vitro. Biomarker analysis on xenograft tumors harvested 3 days following treatment with either Vehicle, T-Dxd, olaparib, or T-Dxd plus olaparib in WHIM6, was also performed, which demonstrated that the addition of olaparib enhanced DNA damage (increased pH2AX), and promoted apoptosis (increased cleaved PARP). Further mechanistic studies in HER2-low TNBC cell lines demonstrated the formation of DNA topoisomerase 1 covalent complexes (TopoIcc) following treatment with T-Dxd. Interestingly, while the formation of Topolcc was reduced with the addition of either ATR or ATM inhibitor, no reduction was observed with the addition of olaparib. Additionally, we observed that combination therapies reduced cell migration in vitro. The combination of olaparib with T-Dxd, in particular, reduced mammosphere formation and Epithelial Mesenchymal Transition (EMT) modulation markers, including SNAIL, SLUG and/or TWIST. Conclusion: Our study demonstrated that the combination of T-Dxd and DDR pathway inhibitors induced additive or synergistic anti-tumor effect in HER2-low TNBC. Our data from the studies of cell lines and PDX models provided preclinical rationale for the combination of T-Dxd and DDR pathway inhibitors in patients with HER2-low TNBC. The olaparib combination showed unique mechanistic characteristics compared with other DDR inhibitors, which are being further examined in additional HER2-low TNBC models. Citation Format: Adrian Gonzalez-Gonzalez, Zhanfang Guo, Alice Meroni, Emily Cybulla, Jeremy Hoog, Alessandro Vindigni, Cynthia Ma. Preclinical study of trastuzumab deruxtecan (T-Dxd; DS-8201a) in combination with DNA damage response pathway inhibitors in HER2-low/Hormone receptor negative breast cancer patient-derived xenograft models [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-17-03.

ObjectiveTo explore Australian chiropractors' and final year students' readiness to identify and support patient's experiencing intimate partner violence (IPV).MethodsThis cross-sectional study used the Chiro-PREMIS, an adaptation of the Physician Readiness to Manage Intimate Partner Violence Survey (PREMIS) to explore chiropractors' and final year students' readiness. Survey responses were analyzed through a lens of Miller's framework for developing clinical competence and chiropractic graduate competencies.ResultsOne hundred forty participants completed the online survey (n = 99 chiropractors and n = 41 students). Reports of practice over the 4 weeks prior to completing the survey showed 21% of chiropractors and 20% of students consulted with patients who had disclosed they were involved in IPV. Thirty-three percent of chiropractors and 27% of students suspected a patient was involved, but that patient did not disclose. Participants report meager training in IPV. Many are unclear about appropriate questioning techniques, documentation, referrals, identifying available resources, and legal literacy. Overall, participants do not “know” about IPV, they do not “know how” to and may not be able to “show how” or “do” when it comes to managing IPV-related clinical scenarios. Further studies are needed to confirm if chiropractors have the appropriate clinical capabilities.ConclusionWith proper preparation, chiropractors have an opportunity to make a positive contribution to this social problem. We anticipate chiropractic-specific discourse surrounding these escalating growing social concerns will highlight the intent of the chiropractic profession to make a substantial contribution to the health care of the Australian public. More studies are needed.

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.

Angelo Di Vincenzo,1 Marnie Granzotto,1 Marika Crescenzi,1 Camilla Costa,1 Stefano Piaserico,2 Vincenzo Vindigni,3 Roberto Vettor,1 Marco Rossato1 1Department of Medicine – DIMED, Clinica Medica 3, University - Hospital of Padova, Padova, Italy; 2Department of Medicine - DIMED, Section of Dermatology, University - Hospital of Padova, Padova, Italy; 3Department of Neurosciences, Clinic of Plastic Reconstructive and Aesthetic Surgery, University – Hospital of Padova, Padova, ItalyCorrespondence: Marco Rossato, Department of Medicine – DIMED, Clinica Medica 3, University Hospital of Padova, Via Giustiniani 2, Padova, 35128, Italy, Tel +39 49 8218746, Fax +39 49 8213332, Email marco.rossato@unipd.itPurpose: Psoriasis is a chronic systemic inflammatory disease involving the production of many pro-inflammatory cytokines derived from immune cells and interacting with different tissues leading to the typical skin lesions. Psoriasis shows a higher prevalence and a worse progression in obese than in lean subjects. The IL-23/IL-17 immune axis has a pivotal role in the pathogenesis of psoriasis and anti-IL-23 monoclonal antibodies are highly effective in its treatment. Since obesity in frequently associated with elevated insulin plasma levels, we have investigated the ability of in vitro differentiated human adipocytes to produce IL-23 at basal conditions and after insulin stimulation.Material and Methods: In vitro differentiated human adipocytes were incubated in the absence and presence of different insulin concentrations and the expression of IL-23 was analyzed by real-time PCR and Western blotting.Results: The results of this study show that in vitro differentiated human adipocytes spontaneously express IL-23 mRNA and protein being stimulated by insulin in a dose-dependent manner. The stimulatory effects of insulin on IL-23 expression were specific since it did not stimulate the expression of other well-known cytokines involved in psoriasis pathogenesis such as Il-22 nor LL-37. Furthermore, lipopolysaccharide did not stimulate IL-23 expression in human adipocytes, thus highlightening the specific effects of insulin in the stimulation of IL-23 expression in human adipocytes.Conclusion: Here we show that human adipocytes spontaneously express IL-23 and that insulin stimulates IL-23 production by these cells in a specific manner as other stimuli, known to be involved in psoriasis pathophysiology, are ineffective. These observations could explain the association between psoriasis and obesity, a condition frequently characterized by a state of insulin hypersecretion.Keywords: adipocyte, human, IL-23, insulin, obesity, psoriasis

SummaryDNA combing and DNA spreading are two central approaches for studying DNA replication fork dynamics genome-wide at single-molecule resolution by distributing labeled genomic DNA on coverslips or slides for immunodetection. Perturbations in DNA replication fork dynamics can differentially affect either leading or lagging strand synthesis, for example in instances where replication is blocked by a lesion or obstacle on only one of the two strands. Thus, we sought to investigate whether the DNA combing and/or spreading approaches are suitable for resolving adjacent sister chromatids during DNA replication, thereby enabling the detection of DNA replication dynamics within individual nascent strands. To this end, we developed a thymidine labeling scheme that discriminates between these two possibilities. Our data suggests that DNA combing resolves single chromatids, allowing the detection of strand-specific alterations, whereas DNA spreading does not. These findings have important implications when interpreting DNA replication dynamics from data obtained by these two commonly used techniques.

We aimed to provide a single, viable and user-friendly operative protocol for preoperative antibiotic prophylaxis that meets the needs of all plastic surgery practitioners.The research was conducted through the abstract and citation databases of peer-reviewed literature Pubmed® (National Center for Biotechnology Information), Medscape® (General Surgery) and Scopus® (Elsevier), comparing existing data from 2010 to 2020. A separated and dedicated research was accomplished for each of 8 macroareas such as: skin and soft tissue, hand, breast, aesthetics, head and neck, trauma, burns and miscellaneous.The findings for each macroareas included the choice of the antibiotic, the route and timing of administration and the clinical applications. Finally, the review has been condensed in an operative algorithm for antibiotic use to apply in each field of plastic surgery.We could provide plastic surgeon an effective, easy-to-use operative protocol for antibiotic prophylaxis in daily activity.

Background Massive weight loss (MWL) is a very common presentation that you may face as a plastic surgeon. Each patient has his own individual criteria, so, you should work according to a well-organized plan, especially when such cases have concerns about their gluteal area contour that were neglected before by many surgeons. A decision-making strategy was used to give a personalized treatment for targeting gluteal region reshaping of MWL patients. Methods This study considered all patients with MWL subjected to buttock reshaping. There was no randomization in treatment; there was a case-by-case assessment. We analyzed the features of the buttocks, the type of surgery performed, the outcomes, and the complications. Results Fifty two patients were included (41 females and 11 males), ages ranged between 21 and 66 years. Demographic data, preoperative body mass index (BMI), duration of surgery, type of surgery, and postoperative complications were collected. Statistically significant improvements were observed in gluteal ptosis and patient satisfaction grades. Conclusion Aesthetic improvement of the buttocks involves either augmentation or contouring that may be obtained by liposculpture, surgical lifting, or combination. Patients with MWL have high expectations and are often treated with multiple procedures. Thus, an easy strategic approach personalized on each patient to treat multiple adjacent areas in one operation is necessary. Adipose tissue distribution, gluteal skin status, and BMI were the main factors that can forcefully affect our plan to guarantee reduction of unpleasant results and complications and improve patient satisfaction.

In the course of science theory, when we deal with the subject of language teaching in the context of semiotic structure principle developments as well as in the course of the media culture and religious sciences, it shows that in numerous contributions concerning this subject area there is a complaint that the aporetic treatment and integration of language and religious history [Sprachgeschichte/Religionsgeschichte] in the sense of an internal and external language and religious history should be taken into account [1]. The associated diachrony of historical linguistics is said to be not only relevant but also sufficiently socially systemic and imminently codependent for its constitution [2]. There is talk of a "step child," of "marginal permanence," and even of a malicious deletion from facultative curricula since the international history of language and language teaching is said to be hardly fruitful, especially in view of a problem-oriented approach, obviously not having any relevance for the present constantly transforming, media- and religion-sociology-oriented reality of life and work (paper presented at the Ecumenical and Pedagogy of Religion Colloquium, "Dimensions of Education," at the Nicolaus Copernicus University in Torun, on October 11, 2007, in Torun). The author of this paper does not wish to join in this lament about the "Geschichtslosigkeit und Religionslosigkeit" [historical unawareness] regarding time and language, with its sustainable effect on international language and religion teaching, since in recent years, there have been some astonishing changes in perspective, signaling a big opportunity in terms of a substantial paradigm shift for international language teaching – the subject of lifelong learning.

Background: The development of obesity-related complications lies in the low-grade inflammatory state consequent to adipocyte dysfunction. The direct involvement of sex hormones in adipose tissue inflammation has been previously suggested, but the evidence is scarce. In this study, we evaluated the effects of sex steroids on the in-vitroexpression of inflammatory mediators in human-derived adipocytes before and after lipopolysaccharide (LPS) exposure. Methods: Human adipocytes were differentiated from the vascular stromal fraction of adipose tissue samples of subjects undergoing abdominoplasty. We evaluated MCP-1, IL-1β, IL-6, and TNF-α gene expression in the presence of the main sex steroids, testosterone (T), and 17β-estradiol (E). Furthermore, we analyzed the effects of adipocytes exposure to the non-aromatizable androgen dihydrotestosterone (DHT), together with the effects of adipocytes pre-incubation with the aromatase inhibitor anastrozole alone (A), and in combination with T (A/T) before incubation with LPS. Results: DHT, but not T, significantly enhanced the LPSinduction of MCP-1, IL-1β, IL-6, and TNF-α. Intriguingly, the exposure of adipocytes with A/T dramatically increased the LPS-induced expression of all considered inflammatory cytokines, even more than a hundred-fold. Conclusions: DHT and A/T dramatically enhance LPS-induced inflammatory cytokine expression in human-derived adipocytes. These results confirm the involvement of sex hormones in adipose tissue inflammation, suggesting a specific role for non-aromatizable androgens as the amplificatory sex hormones of the inflammatory response.

Supplementary Table S1. Comprehensive radiologic, surgical, and pathologic scoring system used to evaluate tumor response to neoadjuvant chemotherapy. Supplementary Table S2. Summary of antibodies used. Supplementary Table S3. Disease characteristics of ovarian cancer patients receiving neoadjuvant chemotherapy and undergoing interval cytoreductive surgery stratified by chemoresponse. Supplementary Table S4. Disease characteristics of ovarian cancer patients receiving neoadjuvant chemotherapy and undergoing interval cytoreductive surgery stratified by high and low serum GAS6 expression prior to neoadjuvant chemotherapy. Supplementary Figure S1. RAD51 foci formation in irradiated ovarian cancer cells. Supplementary Figure S2. GAS6 and AXL expression in four ovarian cancer cell lines. Supplementary Figure S3. Mean combination indexes and dose response curves for paclitaxel and AVB-500 in three ovarian cancer cell lines. Supplementary Figure S4. GAS6/AXL inhibitor AVB-500 improves response to carboplatin and decreases tumor burden in PDX mouse model of ovarian cancer. Supplementary Figure S5. GAS6/AXL inhibitor AVB-500 decreases GAS6 and pAKT expression in mouse tumors. Supplementary Figure S6. Cleaved Caspase 3 levels in OVCAR8 ovarian cancer cells at 24 and 48 hours of treatment. Supplementary Figure S7. Treatment with AVB-500 increases DNA damage. Supplementary Figure S8. Treatment with AVB-500 decreases activation of AKT and does not affect protein expression of 53BP1, AXL, or RAD51. Supplementary Figure S9. Treatment with carboplatin plus AVB-500 decreases pATM and increases pCHK1. Supplementary Figure S10. Treatment with AVB-500 decreases RPA binding and does not affect the cell cycle. Supplementary Figure S11. Treatment with AVB-500 in addition to olaparib increases DNA damage and decreases homologous recombination. Supplementary Figure S12. Proposed mechanism of AVB-500 and carboplatin increasing DNA damage through replication fork perturbation.

Over 80% of women with high-grade serous ovarian cancer (HGSOC) develop tumor resistance to chemotherapy and die of their disease. There are currently no FDA-approved agents to improve sensitivity to first-line platinum- and taxane-based chemotherapy or to PARP inhibitors. Here, we tested the hypothesis that expression of growth arrest–specific 6 (GAS6), the ligand of receptor tyrosine kinase AXL, is associated with chemotherapy response and that sequestration of GAS6 with AVB-S6–500 (AVB-500) could improve tumor response to chemotherapy and PARP inhibitors. We found that GAS6 levels in patient tumor and serum samples collected before chemotherapy correlated with ovarian cancer chemoresponse and patient survival. Compared with chemotherapy alone, AVB-500 plus carboplatin and/or paclitaxel led to decreased ovarian cancer-cell survival in vitro and tumor burden in vivo. Cells treated with AVB-500 plus carboplatin had more DNA damage, slower DNA replication fork progression, and fewer RAD51 foci than cells treated with carboplatin alone, indicating AVB-500 impaired homologous recombination (HR). Finally, treatment with the PARP inhibitor olaparib plus AVB-500 led to decreased ovarian cancer-cell survival in vitro and less tumor burden in vivo. Importantly, this effect was seen in HR-proficient and HR-deficient ovarian cancer cells. Collectively, our findings suggest that GAS6 levels could be used to predict response to carboplatin and AVB-500 could be used to treat platinum-resistant, HR-proficient HGSOC.Implications:GAS6/AXL is a novel target to sensitize ovarian cancers to carboplatin and olaparib. Additionally, GAS6 levels can be associated with response to carboplatin treatment.

Purpose: hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer is still lacking.Experimental Design: hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models.Results: hERG1 was positive in 69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1–G2 grading, I and II tumor—node—metastasis stage, and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the hypoxia inducible factor. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments.Conclusion: Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed. Clin Cancer Res; 20(6); 1502–12. ©2014 AACR.

PDF file - 738K, ADDITIONAL MATERIALS AND METHODS, FIGURES AND TABLES Fig S1- Immunohistochemical detection of hERG1 protein in GC specimens. Fig S2- hERG1 protein expression in GC primary samples. Figure S3- hERG1b characterization in primary GC. Fig S4- hERG1 protein expression in GC cell lines. Fig S5- hERG1USO protein expression in GC cell lines. Fig S6- Effects of the PI3K/Akt inhibition on VEGF-A secretion in AKG cells under normoxic conditions. Fig S7- Immunohistochemical detection of hERG1 protein in GC specimens. Fig S8- Immunohistochemical detection of hERG1 protein in GC specimens. Fig S9- VEGF-A and hERG1 expression in GC samples. Fig S10. Interaction analyses on OS between hERG1 and other clinical and pathological parameters (Forest Plot). Fig S11- Comparison between herg1a mRNA and hERG1A protein expression in GC samples. Table S1- Antibodies used for IHC experiments described in the main text. Table S2- Primer Sequences. Primers were used for methylation analysis and RQ-PCR. Table S3- Cell lines used in the experiments described in the main text. Table S4- hERG1 expression in AKG cells treated with alpha-hERG1 siRNAs and WAY hERG1 blocker. Table S5- VEGF-A and Kv 1.3 expression in AKG cells treated with alpha-hERG1 siRNAs, WAY hERG1 blocker and alpha-vegf-a siRNA. Table S6- Characteristics of patients excluded and included into the statistical analyses and distributions of clinical and pathological variables after multiple imputation of missing values.

Background Due to the high demand of post-bariatric surgeries, the number of litigation cases is rapidly growing. Even if surgical mistakes still represent one of the main causes of medico-legal issues, many disputes depend on what happens in the post-operative course. In this article we analyzed the litigation cases that occurred in our Plastic Surgery Department, the current literature about medico-legal disputes and the importance of the doctor–patient relationship. Patients and methods The medical records of 788 post-bariatric surgeries, the post-operative complications and the related litigation cases from January 2015 to December 2019 were collected, analyzed and compared. Results We performed 380 abdominoplasties, 28 torsoplasties, 65 breast reductions, 99 mastopexies, 94 brachioplasties, 52 thighplasties, 65 liposuctions and 5 facelifts between 2015 and 2019. Eight patients complained of medical issues and claimed for litigation. Despite in all cases the judges highlighted the risk of consent misinterpretation, the payout was granted only in one case. Conclusion Post-bariatric patients often mistake their preoperative condition and consider body contouring procedures as an aesthetic surgery treatment. Patients should be therefore clearly informed about the complexity of body contouring procedures after massive weight loss, which should never be compared to aesthetic surgery. Surgeons should always promote the communication with their patients and build a strong and trustworthy relationship. This attitude will allow to deal more easily with complications and, in the worst situations, with medico-legal litigations. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

The primary method for probing DNA replication dynamics is DNA fiber analysis, which utilizes thymidine analog incorporation into nascent DNA, followed by immunofluorescent microscopy of DNA fibers. Besides being time-consuming and prone to experimenter bias, it is not suitable for studying DNA replication dynamics in mitochondria or bacteria, nor is it adaptable for higher-throughput analysis. Here, we present mass spectrometry–based analysis of nascent DNA (MS-BAND) as a rapid, unbiased, quantitative alternative to DNA fiber analysis. In this method, incorporation of thymidine analogs is quantified from DNA using triple quadrupole tandem mass spectrometry. MS-BAND accurately detects DNA replication alterations in both the nucleus and mitochondria of human cells, as well as bacteria. The high-throughput capability of MS-BAND captured replication alterations in an E. coli DNA damage-inducing gene library. Therefore, MS-BAND may serve as an alternative to the DNA fiber technique, with potential for high-throughput analysis of replication dynamics in diverse model systems.

The flutter phenomenon is a potentially destructive aeroelastic vibration studied for the design of aircraft structures as it limits the flight envelope of the aircraft. The aim of this work is to propose a heuristic design of a piezoelectric actuator-based controller for flutter vibration suppression in order to extend the allowable speed range of the structure. Based on the numerical model of a three degrees of freedom (3DOF) airfoil and taking into account the FEM model of a V-stack piezoelectric actuator, a filtered PID controller is tuned using the population decline swarm optimizer PDSO algorithm, and gain scheduling (GS) of the controller parameters is used to make the control adaptive in velocity. Numerical simulations are discussed to study the performance of the controller in the presence of external disturbances.

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.

Ex-obese patients present with redundancy of abdominal skin and soft tissue due to massive weight loss (MWL). The plastic surgeon can restore the body shape through body contouring procedures. Hence the need to adequately direct patients to body contouring by identifying suitable candidates exists. Our work aims to retrospectively analyze the abdominoplasty complications in our case series to identify associated risk factors and evaluate the effect of combined procedures on abdominoplasty outcomes.We retrospectively investigated predictive factors of abdominoplasty procedure complications on 213 MWL patients who received abdominoplasty with and without rectus sheath plication, abdominal liposuction, and other body contouring procedures. We identified risk and protective factors with univariate and multivariate regression analysis. Furthermore, we assessed the impact of additional procedures on the complication rates.The overall complication rate was 49.8% (26.8% minor complications; 23% major complications). The delayed wound healing rate was 27.7%, and the revision surgery rate was 25.8% (14.7% early revision; 14.2% late revision). These results were compared with literature reports. Several negative predictors emerged as non-modifiable (advanced age, diabetes mellitus, surgical mode of weight loss) or modifiable (preoperative obesity and body mass index (BMI); active smoking; preoperative anemia; use of fibrin glue or quilting sutures). Performing rectus sheath plication improved most of the outcomes. Liposuction of hypochondriac regions and flanks led to increased safety and reduced the risk of surgical dehiscence and delayed wound healing, in contrast to epimesogastric liposuction. The other combined body contouring procedures did not worsen the outcomes, except for poor scarring.Our findings encourage us to continue associating rectus sheath plication, liposuction, and other body contouring surgeries with abdominoplasty. We emphasize the importance of proper patient selection, particularly with regard to anemia, before body contouring surgery in the interests of offering safe surgery and satisfactory results. Further studies are needed to investigate how the optimal BMI cut-off and abstinence from smoking (in terms of time) before surgery reduce postoperative complications.This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors https://www.springer.com/journal/00266 .

Purpose. In modern breast cancer treatment, a growing role has been observed for breast reconstruction together with an increase in clinical indications for postmastectomy radiotherapy (PMRT). Choosing the optimum type of reconstructive technique is a clinical challenge. We therefore conducted a national multicenter study to analyze the impact of PMRT on breast reconstruction. Methods. We conducted a retrospective case-control multicenter study on women undergoing breast reconstruction. Data were collected from 18 Italian Breast Centres and stored in a cumulative database which included the following: autologous reconstruction, direct-to-implant (DTI), and tissue expander/immediate (TE/I). For all patients, we described complications and surgical endpoints to complications such as reconstruction failure, explant, change in type of reconstruction, and reintervention. Results. From 2001 to April 2020, 3116 patients were evaluated. The risk for any complication was significantly increased in patients receiving PMRT (aOR, 1.73; 95% CI, 1.33–2.24; p < 0.001 ). PMRT was associated with a significant increase in the risk of capsular contracture in the DTI and TE/I groups (aOR, 2.24; 95% CI, 1.57–3.20; p < 0.001 ). Comparing type of procedures, the risk of failure (aOR, 1.82; 95% CI, 1.06–3.12, p = 0.030 ), explant (aOR, 3.34; 95% CI, 3.85–7.83, p < 0.001 ), and severe complications (aOR, 2.54; 95% CI, 1.88–3.43, p < 0.001 ) were significantly higher in the group undergoing DTI reconstruction as compared to TE/I reconstruction. Conclusion. Our study confirms that autologous reconstruction is the procedure least impacted by PMRT, while DTI appears to be the most impacted by PMRT, when compared with TE/I which shows a lower rate of explant and reconstruction failure. The trial is registered with NCT04783818, and the date of registration is 1 March, 2021, retrospectively registered.

DNA topoisomerase 1 (TOP11) inhibitors are mainstays of anticancer therapy. These drugs trap TOP1 on DNA, stabilizing the TOP1-cleavage complex (TOP1-cc). The accumulation of TOP1-ccs perturbs DNA replication fork progression, leading to DNA breaks and cell death. By analyzing the genomic occupancy and activity of TOP1, we show that cells adapt to treatment with multiple doses of TOP1 inhibitor by promoting the degradation of TOP1-ccs, allowing cells to better tolerate subsequent doses of TOP1 inhibitor. The E3-RING Cullin 3 ligase in complex with the BTBD1 and BTBD2 adaptor proteins promotes TOP1-cc ubiquitination and subsequent proteasomal degradation. NEDDylation of Cullin 3 activates this pathway, and inhibition of protein NEDDylation or depletion of Cullin 3 sensitizes cancer cells to TOP1 inhibitors. Collectively, our data uncover a previously unidentified NEDD8–Cullin 3 pathway involved in the adaptive response to TOP1 inhibitors, which can be targeted to improve the efficacy of TOP1 drugs in cancer therapy.

DNA is an excellent programmable polymer for the generation of self-assembled multivalent nanostructures useful for biomedical applications. Herein, we developed (i) folate-functionalized nanocages (Fol-NC), very efficiently internalized by tumor cells overexpressing the α isoform of the folate receptor; (ii) AS1411-linked nanocages (Apt-NC), internalized through nucleolin, a protein overexpressed in the cell surface of many types of cancers; and (iii) nanostructures that harbor both folate and AS1411 aptamer functionalization (Fol-Apt-NC). We analyzed the specific miRNA silencing activity of all types of nanostructures harboring miRNA sequestering sequences complementary to miR-21 and the cytotoxic effect when loaded with doxorubicin in a drug-resistant triple-negative breast cancer cell line. We demonstrate that the presence of folate as a targeting ligand increases the efficiency in miR-21 silencing compared to nanocages functionalized with AS1411. Double-functionalized nanocages (Fol-Apt-NC), loaded with doxorubicin, resulted in an increase of over 51% of the cytotoxic effect on MDA-MB-231 cells compared to free doxorubicin, demonstrating, besides selectivity, the ability of nanocages to overcome Dox chemoresistance. The higher efficiency of the folate-functionalized nanocages is due to the way of entrance, which induces more than four times higher intracellular stability and indicates that the folate-mediated route of cell entry is more efficient than the nucleolin-mediated one when both folate and AS1411 modifications are present.

High-fidelity DNA replication is critical for the faithful transmission of genetic information to daughter cells. Following genotoxic stress, specialized DNA damage tolerance pathways are activated to ensure replication fork progression. These pathways include translesion DNA synthesis, template switching and repriming. In this Review, we describe how DNA damage tolerance pathways impact genome stability, their connection with tumorigenesis and their effects on cancer therapy response. We discuss recent findings that single-strand DNA gap accumulation impacts chemoresponse and explore a growing body of evidence that suggests that different DNA damage tolerance factors, including translesion synthesis polymerases, template switching proteins and enzymes affecting single-stranded DNA gaps, represent useful cancer targets. We further outline how the consequences of DNA damage tolerance mechanisms could inform the discovery of new biomarkers to refine cancer therapies.

DNA replication forks are tightly controlled by a large protein network consisting of well-known core regulators and many accessory factors which remain functionally undefined. In this study, we report previously unknown nuclear functions of the actin-binding factor profilin-1 (PFN1) in DNA replication, which occur in a context-dependent fashion and require its binding to poly-L-proline (PLP)-containing proteins instead of actin. In unperturbed cells, PFN1 increases DNA replication initiation and accelerates fork progression by binding and stimulating the PLP-containing nucleosome remodeler SNF2H. Under replication stress, PFN1/SNF2H increases fork stalling and functionally collaborates with fork reversal enzymes to enable the over-resection of unprotected forks. In addition, PFN1 binds and functionally attenuates the PLP-containing fork protector BODL1 to increase the resection of a subset of stressed forks. Accordingly, raising nuclear PFN1 level decreases genome stability and cell survival during replication stress. Thus, PFN1 is a multi-functional regulator of DNA replication with exploitable anticancer potential.

We are sitting on the cusp of the bioengineered breast era, in which implant-based breast reconstruction is seeing a growing trend and biotechnology research progressively empowers clinical practice. As never before, the choice of biomaterials has acquired great importance for achieving reconstructive outcomes, and the increase in the use of acellular dermal matrices (ADMs) in the field of senology tells us a story of profound upheaval and progress. With the advent of prepectoral breast reconstruction (PPBR), plenty of devices have been proposed to wrap the silicone prosthesis, either completely or partially. However, this has caused a great deal of confusion and dissent with regard to the adoption of feasible reconstructive strategies as well as the original scientific rationale underlying the prepectoral approach. Braxon® is the very first device that made prepectoral implant positioning possible, wrapping around the prosthesis and exerting the proven ADM regenerative potential at the implant–tissue interface, taking advantage of the body's physiological healing mechanisms. To date, the Braxon® method is among the most studied and practiced worldwide, and more than 50 publications confirm the superior performance of the device in the most varied clinical scenarios. However, a comprehensive record of the working of this pioneering device is still missing. Therefore, our aim with this review is to lay a structured knowledge of surgery with BRAXON® and to provide a decision-making tool in the field of PPBR through a complete understanding on the very first device for prepectoral, one decade after its introduction.

Context Nationwide data on children diagnosed with craniopharyngioma (CP) are not available in Italy. Objective This work aimed to identify patients’ characteristics, type of surgical approach, complications and recurrences, number of pituitary deficits, and number of patients starting growth hormone (GH) treatment. Methods A retrospective multicenter collection took place of 145 patients aged 0 to 18 years who underwent surgery for CP between 2000 and 2018, and followed up in 17 Italian centers of pediatric endocrinology. Results Age at diagnosis was 8.4 ± 4.1 years. Duration of symptoms was 10.8 ± 12.5 months and headache was most frequent (54%), followed by impaired growth (48%) and visual disturbances (44%). Most lesions were suprasellar (85%), and histology was adamantinomatous in all cases but two. Surgical approach was transcranial (TC) in 67.5% of cases and transsphenoidal (TS) in 31.%. The TC approach was prevalent in all age groups. Postsurgery complications occurred in 53% of cases, with water-electrolyte disturbances most frequent. Radiotherapy was used in 39% of cases. All patients but one presented with at least one hormone pituitary deficiency, with thyrotropin deficiency most frequent (98.3%), followed by adrenocorticotropin (96.8%), arginine vasopressin (91.1%), and GH (77.4%). Body mass index (BMI) significantly increased over time. A hypothalamic disturbance was present in 55% of cases. GH therapy was started during follow-up in 112 patients at a mean age of 10.6 years, and 54 developed a recurrence or regrowth of the residual lesion. Conclusion CP is often diagnosed late in Italy, with TC more frequent than the TS surgical approach. Postsurgery complications were not rare, and hypopituitarism developed almost in all cases. BMI shows a tendency to increase overtime.

Regenerative medicine and surgery is a rapidly expanding branch of translational research in tissue engineering, cellular and molecular biology.To date, the methods to improve cell intake, survival, and isolation need to comply with a complex and still unclear regulatory frame, becoming everyday more restrictive and often limiting the effectiveness and outcome of the therapeutic choices. Thus, the authors developed a novel 360° regenerative strategy based on the synergic action of several new components called the bioactive composite therapies (BACTs) to improve grafted cells intake, and survival in total compliance with the legal and ethical limits of the current regulatory frame.The rationale at the origin of this new technology is based on the evidence that cells need supportive substrate to survive in vitro and this observation, applying the concept of translational medicine, is true also in vivo. Bioactive composite mixtures (BACMs) are tailor-made bioactive mixtures containing several bioactive components that support cells’ survival and induce a regenerative response in vivo by stimulating the recipient site to act as an in situ real bioreactor. Many different tissues have been used in the past for the isolation of cells, molecules, and growth factors, but the adipose tissue and its stromal vascular fraction (SVF) remains the most valuable, abundant, safe, and reliable source of regenerative components and particularly of adipose-derived stems cells (ADSCs). The role of plastic surgeons as the historical experts in all the most advanced techniques for harvesting, manipulating, and grafting adipose tissue is fundamental in this constant process of expansion of regenerative procedures. In this article, we analyze the main causes of cell death and the strategies for preventing it, and we present all the technical steps for preparing the main components of BACMs and the different mixing modalities to obtain the most efficient regenerative action on different clinical and pathological conditions. The second section of this work is dedicated to the logical and sequential evolution from simple bioactive composite grafts (BACGs) that distinguished our initial approach to regenerative medicine, to BACTs where many other fundamental technical steps are analyzed and integrated for supporting and enhancing the most efficient regenerative activity. Level of Evidence: Not gradable

Background Social cognition and temperamental and interpretative styles could play a role in the outcome of bariatric surgery. This study aims to assess preliminary evidence about how obesity surgery patients evaluate social inclusion and exclusion through a ball-tossing game called Cyberball, looking at the influence of early maladaptive schemas. Methods Thirty-four patients with a history of obesity surgery interventions and 44 controls were recruited for this study. A psychological evaluation was performed before and after the Cyberball task with self-report questionnaires. Results In the ostracism condition, significant differences were seen across all the patients’ fundamental psychological needs with less perceived ostracization (p = 0.001) even if they recognized less interaction via fewer ball tosses than controls. Moreover, the ostracism paradigm resulted in patients experiencing a higher urge to binge (p = 0.010) and a higher urge to restrain (p = 0.012) than controls. Looking at differences due to the Cyberball paradigm applied, clear differences emerged only between controls subgroups at the specific self-report scales applied, corroborating the reduced perception of the exclusion. As evidenced by the schema domains, the study found a connection between the impaired limits-schema domain and the drive to binge. Conclusion The results show that obesity surgery patients reported different effects of the Cyberball task than controls. Different possible interpretations are discussed, and future directions for studies are exposed, both for the evaluation of social interactions effects and in the assessment of the role of specific cognitive schemas. Level of evidence Level III: evidence obtained from well-designed cohort or case–control analytic studies.

No robust evidence is provided by literature regarding the management of intracranial hypertension following severe traumatic brain injury (TBI). This is mostly due to the lack of prospective randomized controlled trials (RCTs), the presence of studies containing extreme heterogeneously collected populations and controversial considerations about chosen outcome. A scientific society should provide guidelines for care management and scientific support for those areas for which evidence-based medicine has not been identified. However, RCTs in severe TBI have failed to establish intervention effectiveness, arising the need to make greater use of tools such as Consensus Conferences between experts, which have the advantage of providing recommendations based on experience, on the analysis of updated literature data and on the direct comparison of different logistic realities. The Italian scientific societies should provide guidelines following the national laws ruling the best medical practice. However, many limitations do not allow the collection of data supporting high levels of evidence for intracranial pressure (ICP) monitoring and decompressive craniectomy (DC) in patients with severe TBI. This intersociety document proposes best practice guidelines for this subsetting of patients to be adopted on a national Italian level, along with joint statements from "TBI Section" of the Italian Society of Neurosurgery (SINch) endorsed by the Neuroanesthesia and Neurocritical Care Study Group of the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI). Presented here is a recap of recommendations on management of ICP and DC supported a high level of available evidence and rate of agreement expressed by the assemblies during the more recent consensus conferences, where members of both groups have had a role of active participants and supporters. The listed recommendations have been sent to a panel of experts consisting of the 107 members of the "TBI Section" of the SINch and the 111 members of the Neuroanesthesia and Neurocritical Care Study Group of the SIAARTI. The aim of the survey was to test a preliminary evaluation of the grade of predictable future adherence of the recommendations following this intersociety proposal. The following recommendations are suggested as representing best clinical practice, nevertheless, adoption of local multidisciplinary protocols regarding thresholds of ICP values, drug therapies, hemostasis management and perioperative care of decompressed patients is strongly recommended to improve treatment efficiency, to increase the quality of data collection and to provide more powerful evidence with future studies. Thus, for this future perspective a rapid overview of the role of the multimodal neuromonitoring in the optimal severe TBI management is also provided in this document. It is reasonable to assume that the recommendations reported in this paper will in future be updated by new observations arising from future trials. They are not binding, and this document should be offered as a guidance for clinical practice through an intersociety agreement, taking in consideration the low level of evidence.

Background Chiropractic is a mostly privatised health profession within Australia, with people experiencing disadvantage typically having limited access due to financial barriers. However, some universities within Australia offer community outreach clinics where students provide chiropractic care to people living with disadvantage. This demographic experiences higher rates of chronic conditions including musculoskeletal complaints and requires subsidisation to access privatised care. This need also offers opportunity for the chiropractic profession to work within community healthcare teams. A mixed-methods observational study was used to investigate how the unique setting of a student chiropractic community clinic may influence the experience and outcomes of those who attend. Methods Three patient-reported outcome measures (PROMs) investigated client outcomes: Measure Yourself Medical Outcome Profile (MYMOP); European Five Domain Five Level Quality of Life Questionnaire (EQ-5D-5L); and the Patient Enablement Instrument. The PROMs data were analysed descriptively and inferentially. Interviews were conducted with clients who had received chiropractic care, chiropractic students, clinical supervisors and staff of the centre. Interview data were coded using thematic analysis, and themes were formed using Bronfenbrenner’s socio-ecological systems framework and non-participant observations. Results Thirty-seven participants completed baseline PROMs and 17 completed follow-ups after four treatments. Seventy-two percent of participants nominated their primary complaint as chronic. Significant change was noted in general health and wellbeing for the MYMOP, pain and disability for the EQ-5D-5L and index scores for the EQ-5D-5L suggested improved health and wellbeing. Most clients experienced higher levels of enablement post treatment. Twelve participants were interviewed (four were clients), with five themes emerging from the interview data. Clients reported their lived experiences impacted their health problems and attending the clinic offered benefits beyond improvement of pain and disability. Conclusions Interview data suggested that these benefits were due to a combination of therapy, the setting and the relationships formed within that setting. Complementing this, PROM data suggested clients experienced better levels of health and wellbeing and decreased levels of pain and disability. Findings indicated that people who experienced disadvantage may receive broader benefits from attending community centres offering chiropractic care. Services such as chiropractic may be complementary in meeting the healthcare needs of those experiencing disadvantage.

DNA topoisomerases resolve topological stress by introducing transient single- or double-strand breaks into the DNA duplex. This reaction requires the covalent binding of topoisomerases to DNA while the topological stress is being released. This transient intermediate is known as topoisomerase-covalent complex and represents the target of many anti-cancer drugs. Here, we describe a protocol to quantitatively detect topoisomerase-covalent complexes in vivo, called RADAR (rapid approach to DNA adduct recovery). DNA and protein-DNA covalent complexes are rapidly isolated from cells through chaotropic extraction. After normalization, samples are loaded on a slot blot, and the covalent complexes are detected using specific topoisomerase antibodies. In addition to being fast and robust, this assay produces quantitative results. Consequently, the RADAR assay can be applied to investigate the topoisomerase-covalent complex biology, including the effect of specific topoisomerase inhibitors. Finally, the same assay can be more generally applied to study covalent complexes of other enzymes with DNA.

We are sitting on the cusp of the bioengineered breast era, in which implant-based breast reconstruction is seeing a growing trend and biotechnology research progressively empowers clinical practice. As never before, the choice of biomaterials has acquired great importance for achieving reconstructive outcomes, and the increase in the use of acellular dermal matrices (ADMs) in the field of senology tells us a story of profound upheaval and progress. With the advent of prepectoral breast reconstruction (PPBR), plenty of devices have been proposed to wrap the silicone prosthesis, either completely or partially. However, this has caused a great deal of confusion and dissent with regard to the adoption of feasible reconstructive strategies as well as the original scientific rationale underlying the prepectoral approach. Braxon

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.

Background Virtual radiography provides students with an opportunity to practise their clinical skills in patient positioning and evaluating radiographic images. The purpose of this pilot study was to introduce Projection VR™, a software radiography simulation program, into a student chiropractic program and evaluate its potential application as a teaching and learning tool. Methods Undergraduate chiropractic students, enrolled in a radiographic course (unit within the chiropractic program), were invited to attend a scheduled laboratory where they were introduced to, and undertook purposefully designed activities using the radiography simulation. At the end of this activity, students were asked to complete an online survey (see Virtual Radiography Survey) to describe their experiences of the educational value of the software program. Descriptive statistics were used to evaluate outcomes. Content analysis was performed for free-text comments provided by respondents with key themes provided by the predetermined quantitative categories of the questionnaire. Results Responses were received from 44 out of the 47 students who attended the scheduled laboratory (response rate 92%). Overall students were positive about this simulation identifying that it was easy to use (95%) and that they could control the equipment as needed (95%). The main reported benefits included students being enabled to repeat tasks until they were satisfied with the results (98%) and being able to quickly assess images and determine if changes needed to be made (98%). Participants reported improvement in their understanding of the effect of exposure factors on patient radiation dose (93%) as well as their technical image evaluation (84%) and problem-solving skills (80%). Conclusions The results of this study suggest that virtual radiography is a valuable complementary resource in providing chiropractic students with radiographic knowledge and skills.

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.

Reduction mammaplasty is one of the most popular plastic surgery procedures requested by patients. The areola holding flap can be sculpted using a variety of methods that have evolved over time dependent on vascularity. Our institution has always employed the vertical bipedicle technique proposed by Mckissock, and we still favor it over other methods for larger breasts. In this study, we examined the case-study data from the Padua University Hospital's Unit of Plastic and Reconstructive Surgery from January 2009 to December 2021. The rate of complications among patients who received breast reduction using the McKissock technique and all other procedures carried out at our facility was compared. We identified 90 postoperative problems in all (affecting 42.65% of the patients) and categorized them using the Clavien Dindo system. The groups were comparable in age, BMI, and follow-up time. Similar findings emerged from the study of the single groups' complication rate. The statistical analysis did not reveal any appreciable variation in total complications or scar quality across groups. Therefore, in order to guarantee NAC survival, a stable shape, and a full upper pole, we think it is preferable to bind more than one pedicle in cases of very large breasts. Based on the results of our experience, we also recommend the McKissock approach as the first option for patients with large and ptotic breasts, particularly those who have undergone bariatric surgery and need a full upper pole and a stable outcome.

New plant breeding techniques (NPBTs) are seen as promising and innovative tools to achieve food security and food safety. Biotechnological innovations have great potential to address sustainable food development, and they are expected in the near future to play a critical role in feeding a growing population without exerting added pressure on the environment. There is, however, a considerable debate as to how these new techniques should be regulated and whether some or all of them should fall within the scope of EU legislation on genetically modified organisms (GMOs), despite the product obtained being free from genes foreign to the species. In the EU, the adoption of these methods does not rely only on the scientific community but requires social acceptance and a political process that leads to an improved regulatory framework. In this paper, we present the results of an online survey carried out in Italy with 700 randomly selected participants on consumer attitudes towards food obtained by NPBTs. By applying the decision tree machine learning algorithm J48 to our dataset, we identified significant attributes to predict the main drivers of purchasing such products. A classification model accuracy assessment has also been developed to evaluate the overall performance of the classifier. The result of the model highlighted the role of consumers’ self-perceived knowledge and their trust in the European approval process for NPBT, as well as the need for a detailed label. Our findings may support decision makers and underpin the development of NPBT products in the market.

A rare case of agranulocytosis due to Methimazole administration for Basedow disease is presented. After 30 days since the therapy beginning a 45 year old female patient has developed a necrotizing fasciitis on both legs, with muscle bellies and Achille’s tendon exposure. Immediate surgical debridement was necessary to save her life and control the progression of infection. Several plastic surgery procedures were performed to accomplish wounds healing (vacuum-assisted closure therapy, dermal substitute, free flap, skin graft), and after 75 days the patient was discharged. An intensive rehabilitation program permitted a complete functional recovery. After 12 months a reshaping procedure was performed to improve right leg and ankle contour. The close cooperation between endocrinologist and surgeon revealed to be essential to perform a safe surgery and to permit the return to the job and daily activities.

Background Due to the great impact of bariatric surgery on the overweight epidemic, the number of post-bariatric body-contouring procedures is constantly increasing worldwide. The portable incisional negative pressure wound therapy (piNPWT) is a promising medical device for accelerating wounds closure and controlling post-operative complication, which have been shown promising results in post-bariatric population. We aimed to evaluate the role of piNPWT in optimizing wound healing and controlling post-operative complications after a post-bariatric brachioplasty. Patients and Methods 26 post-bariatric female patients who underwent a brachioplasty followed by either a piNPWT (14 cases) or a standard wound treatment (12 controls) were analyzed. The number of post-operative dressing changes, the rate of local post-operative complications (re-operation, hematoma and serosa development, dehiscence and necrosis), the time to dry as well as the scar quality and hospitalization length were evaluated. Results None of the patients prematurely stopped treatment with piNPWT due to intolerance. The piNPWT patient group showed a significant lower healing time as well as a significant reduction of the number of post-operative dressing changes and hospital stay. Despite the scarring process was excellent from the functional point of view in the long term, we noticed a higher rate of hyperchromic scarring at 90 days after surgery. Conclusion The piNPWT is a cost-effective and user-friendly medical tool that increase and promote wound healing. We suggest the use of this device in post-bariatric patients who undergo a brachioplasty, especially if there is the need to minimize the number of post-operative dressing changes. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266.

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.

In this article, we tried to take stock of the state of the art in ultrasonic-assisted lipoplasty focusing on its most recent technologic advances and in the newest clinical applications, such as overweight, obesity, breast surgery and regenerative medicine. Great space was devoted to the analysis and clarification of the most common myths and legends related to this intriguing technique.