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Purpose: Uterine leiomyomas are benign uterine tumors. The choice of surgical treatment is guided by patient's age, desire to preserve fertility or avoid "radical" surgical interventions such as hysterectomy. In laparotomy, the issue of extracting the fibroid from the cavity does not arise. However, in laparoscopy and robotic surgery, this becomes a challenge. The aim of the present study was to determine the optimal surgical approach for fibroid extraction following laparoscopic or robotic myomectomy in terms of postoperative pain, extraction time, overall surgical time, scar size, and patient satisfaction., Methods: A total of 51 patients met the inclusion criteria and were considered in our analysis: 33 patients who had undergone the "ExCITE technique" (Group A), and 18 patients a minilaparotomy procedure (Group B), after either simple myomectomy, multiple myomectomy, supracervical hysterectomy, or total hysterectomy. The diagnosis of myoma was histologically confirmed in all cases., Results: Regarding the postoperative pain evaluation, at 6 h, patients reported 4 [3-4] vs 6 [5.3-7] on the VAS in Group A and B, as well as at 12 h, 2 [0-2] vs 3.5 [2.3-4] in Group A and B, respectively: both differences were statistically significant (p < 0.001). No statistically significant difference at 24 h from surgery was found. All patients in Group A were satisfied with the ExCITE technique, while in Group B only 67% of them. The length of the hospital stay was significantly shorter in Group A as compared to Group B (p = 0.007). In terms of the operative time for the extraction of the surgical specimen, overall operative time, and the scar size after the surgery, there was a statistically significant difference for those in Group A., Conclusion: The ExCITE technique does not require specific training and allows the surgeon to offer a minimally invasive surgical option for patients, with also an aesthetic result. It is a safe and standardized approach that ensures tissue extraction without the need for mechanical morcellation., (© 2023. The Author(s).)

Introduction: Minimally invasive procedures performed in laparoscopy, such as salpingectomy for ectopic pregnancy, can be combined with a minimally invasive anesthesia. The aim of this study was to assess the feasibility and the intraoperative and postoperative outcomes of laparoscopic surgery for ectopic pregnancy under spinal anesthesia (SA) compared to general anesthesia (GA) from the point of view of the surgeon, anesthesiologist, and patient., Methods: A retrospective cohort study was performed at DAI Materno Infantile of AOU Federico II of Naples, analyzing all medical records of women who met the inclusion criteria between April 2020 and April 2023. Eighty-two women (35 under SA in group A and 47 under GA in group B) undergone elective or emergency laparoscopic salpingectomy for ectopic tubal or ovarian pregnancy were included., Results: Patients in group A reported less pain at 0 h (adjusted mean difference: -1.5; 95% CI: -2.3 to -0.7; p &lt; 0.001) and after 6 h (adjusted mean difference: -1.1; 95% CI: -2.0 to -0.3; p = 0.01) while no statistically significant differences between the two groups at 12 and 24 h after surgery. No differences were observed among the type of analgesic and during the postoperative observation time, except for paracetamol at 0 h in group B. A faster resumption of bowel motility, patient's mobilization, and a shorter hospital stay were observed in group A compared to group B. Also greater odds of returning faster to daily activities emerged in group A (adjusted OR: 5.39; 95% CI: 1.77-16.37). A greater number of patients in group A were satisfied with the entire procedure compared to those of group B (33 [94.3%] vs. 37 [78.7%]). The general surgeon satisfaction was always very good or excellent in group A. Finally, all surgical steps were well tolerated in group A., Conclusion: In specific settings, SA is a feasible and safe procedure for the laparoscopic treatment of ectopic pregnancy., (© 2023 S. Karger AG, Basel.)

Despite the existing body of evidence, there is still limited knowledge about the impact of SARS-CoV-2 positivity on delivery outcomes. We aimed to assess the impact of SARS-CoV-2 infection in women who gave birth at the University Hospital "Federico II" of Naples, Italy, between 2020 and 2021. We conducted a retrospective single-center population-based observational study to assess the differences in the caesarean section and preterm labor rates and the length of stay between women who tested positive for SARS-CoV-2 and those who tested negative at the time of labor. We further stratified the analyses considering the time period, dividing them into three-month intervals, and changes in SARS-CoV-2 as the most prevalent variant. The study included 5236 women with 353 positive cases. After vaccination availability, only 4% had undergone a complete vaccination cycle. The Obstetric Comorbidity Index was higher than 0 in 41% of the sample. When compared with negative women, positive ones had 80% increased odds of caesarean section, and it was confirmed by adjusting for the SARS-CoV-2 variant. No significant differences were found in preterm birth risks. The length of stay was 11% higher in positive cases but was not significant after adjusting for the SARS-CoV-2 variant. When considering only positive women in the seventh study period (July-September 2021), they had a 61% decrease in the odds of receiving a caesarean section compared to the fourth (October-December 2020). Guidelines should be implemented to improve the safety and efficiency of the delivery process, considering the transition of SARS-CoV-2 from pandemic to endemic. Furthermore, these guidelines should aim to improve the management of airborne infections in pregnant women.

Cervical cancer (CC) is the fourth most common cancer among women worldwide. The aim of this study is to focus on the state of the art of CC prevention, early diagnosis, and treatment and, within the latter, the role of surgery in the various stages of the disease with a focus on the impact of the LACC study (Laparoscopic Approach to Cervical Cancer trial) on the scientific debate and clinical practice. We have discussed the controversial application of minimally invasive surgery (MIS) for tumors < 2 cm and the possibility of fertility-sparing surgery on young women desirous of pregnancy. This analysis provides support for surgeons in the choice of better management, including patients with a desire for offspring and the need for sentinel node biopsy (SNB) rather than pelvic lymphadenectomy for tumors < 4 cm, and without suspicious lymph nodes' involvement on imaging. Vaccines and early diagnosis of pre-cancerous lesions are the most effective public health tool to tackle cervical cancer worldwide.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has been extensively studied in patients with peritoneal carcinomatosis, and it holds promise as a therapeutic strategy, but its role remains elusive. The aim of this study was to assess the existing evidence for the use or not of HIPEC in primary debulking surgery (PDS), interval debulking surgery (IDS), and recurrent ovarian cancer (ROC), evaluated in terms of survival rates and post-surgical morbidity., Methods: Medline, Pubmed, Cochrane, and Medscape were systematically searched for any article comparing the use of HIPEC treatment with any other therapy in patients with ovarian cancer in PDS, IDS, and ROC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were followed. We only considered English-language published studies., Results: We included 14 studies, including two RCTs with a total of 1813 women, published between 2003 and 2023 with a recruitment period between 1998 and 2020. In PDS, there were no differences in progression-free survival (PFS) between HIPEC and controls [MD -5.53 months [95% CI -19.91 to 8.84 months]; I 2 = 96%]. Conversely, in patients treated with NACT, pooled results showed a significant survival advantage in terms of progression-free survival (PFS) and overall survival (OS) in the combined HIPEC plus IDS group rather than surgery alone [PFS: MD 4.68 months (95% CI 3.49 to 5.86 months, I 2 = 95%); OS: MD 11.81 months (95% CI 9.34 to 14.27 months); I 2 = 97%]. Concerning ROC patients, pooled MD did not show either a significant PFS difference between intervention and controls [MD 2.68 months (95% CI 433 to 9.70 months); I 2 = 95%], and OS significant difference (MD 6.69 months [95% CI -9.09 to 22.47 months]; I 2 = 98%). Severe post-operative complications (≥grade 3) were available in 10 studies, accounting for 1108 women. Overall, there was a slightly but significantly increased risk with the combined approach compared to controls [RR 1.26 (95% CI 1.02 to 1.55); I 2 = 0%]., Conclusions: The combination of HIPEC with cytoreductive surgery prolongs OS and PFS in advanced epithelial ovarian cancer after NACT with acceptable morbidity. However, additional trials are still needed to determine the effectiveness of HIPEC in primary and recurrence settings. In the era of personalized medicine, the correlation between the efficacy of HIPEC and biological and molecular findings represents a challenge for the future of ovarian cancer.

Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation promotes the expression of antioxidant enzymes in response to rising oxidative stress, resulting in reactive oxygen species (ROS) detoxification and playing a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Moreover, the biological effects of Nrf2 pathway activation contribute to reducing apoptosis and enhancing cell survival. The activity of Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1). Prompted by the recent results reporting the impact of xanthone metabolites on oxidative stress, cancer, and inflammation, the antioxidant properties of xanthones isolated from Garcinia mangostana (γ-mangostin, α-mangostin, 8-deoxygartanin, demethylcalabaxanthone, garcinone D) were assessed. In particular, the capability of these natural products to disrupt the interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2), triggering the activation of the Nrf2-mediated pathway, was evaluated using molecular docking experiments and in vitro tests. The modulation of some key Nrf2-related mediators like glutathione (GSH) and lactate dehydrogenase (LDH) to highlight a possible direct antioxidant effect was investigated. Among the tested compounds, demethylcalabaxanthone showed an indirect antioxidant effect, as corroborated by a Western blot assay, displaying a significant increase in the translocated protein upon its administration.

Here we report a detailed structure-activity relationship (SAR) study related to [1,2,4]triazolo[4,3-a]quinoxaline-based compounds targeting the reader module of bromodomain containing-protein 9 (BRD9). 3D structure-based pharmacophore models, previously introduced by us, were here employed to evaluate a second generation of compounds, exploring different substitution patterns on the heterocyclic core. Starting from the promising data obtained from our previously identified [1,2,4]triazolo[4,3-a]quinoxaline-based compounds 1-4, the combination of in silico studies, chemical synthesis, biophysical and in vitro assays led to the identification of a new set of derivatives, selected for thoroughly exploring the chemical space of the bromodomain binding site. In more details, the investigation of different linkers at C-4 position highlighted the amine spacer as mandatory for the binding with the protein counterpart and the crucial role of the alkyl substituents at C-1 for increasing the selectivity toward BRD9. Additionally, the importance of a hydrogen bond donor group, critical to anchor the ZA region and required for the interaction with Ile53 residue, was inferred from the analysis of our collected results. Herein we also propose an optimization and an update of our previously reported "pharm-druglike2" 3D structure-based pharmacophore model, introducing it as "pharm-druglike2.1". Compounds 24-26, 32, 34 and 36 were identified as new valuable BRD9 binders featuring IC 50 values in the low micromolar range. Among them, 24 and 36 displayed an excellent selectivity towards BRD9 and a good antiproliferative effect on a panel of leukemia models, especially toward CCRF-CEM cell line, with no cytotoxicity on healthy cells. Notably, the interaction of 24 and 36 with the bromodomain and PHD finger-containing protein 1 (BRPF1) also emerged, disclosing them as new and unexplored dual inhibitors for these two proteins highly involved in leukemia. These findings highlight the potential for the identification of new attractive dual epidrugs as well as a promising starting point for the development of chemical degraders endowed with anticancer activities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Herein, we report the development of a new series of histone deacetylase inhibitors (HDACi) containing a 2-substituted 1,5-benzothiazepine scaffold. First, a virtual combinatorial library (∼1.6 × 10 3 items) was built according to a convenient synthetic route, and then it was submitted to molecular docking experiments on seven HDACs isoforms belonging to classes I and II. Integrated computational filters were used to select the most promising ones that were synthesized through an optimized approach, also amenable to generating both racemic and enantioenriched benzothiazepine-based derivatives. The obtained compounds showed potent HDAC inhibitory activity, especially those containing the sulphone moiety, endowed with IC 50 in the nanomolar range. In addition, in vitro outcomes of our synthesized compounds demonstrated a cytotoxic effect on U937 and HCT116 cell lines and an arrest in the G2/M phase (13 ≤ IC 50  ≤ 18 µM). Finally, Western blot analyses outlined the modulation of the histone acetyl markers such as H3K9/14, acetyl-tubulin, and the apoptotic indicator p21 in both cancer cell lines, disclosing a good HDAC inhibitor activity exerted by the designed items. Given the key role of HDACs in many cellular pathways, which makes these enzymes appealing and "hot" drug targets, our findings highlighted the importance of these 2-substituted 1,5-benzothiazepine-based compounds (both in the reduced and oxidized version) for the development of novel epidrugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cesarean scar ectopic pregnancy is a type of ectopic pregnancy in which the fertilized egg is implanted in the muscle or fibrous tissue of the scar after a previous cesarean delivery. The condition can be catastrophic if not managed on time and can lead to significant morbidity and mortality. Several approaches have been studied for the management of cesarean scar ectopic pregnancy in women who opted for termination of pregnancy with no consensus on the best treatment modality reached so far., Objective: This study aimed to compare the success rate of hysteroscopic resection vs ultrasound-guided dilation and evacuation for the treatment of cesarean scar ectopic pregnancy., Study Design: This was a parallel group, nonblinded, randomized clinical trial conducted at a single center in Italy. Women with singleton gestations at <8 weeks and 6 days of gestation were included in the study. Inclusion criteria were women with a cesarean scar ectopic pregnancy with positive embryonic heart activity who opted for termination of pregnancy. Patients were randomized 1:1 to receive either hysteroscopic resection (ie, intervention group) or ultrasound-guided dilation and evacuation (ie, control group). Both groups received 50 mg/m 2 of methotrexate intramuscularly at the time of randomization (day 1) and another dose at day 3. A third dose of methotrexate was planned in case of persistence of positive fetal heart activity at day 5. Participants received either ultrasound-guided dilation and evacuation or hysteroscopic resection from 1 to 5 days after the last dose of methotrexate. Hysteroscopic resection was performed under spinal anesthesia using a 15 Fr bipolar mini-resectoscope. Dilation and evacuation were performed by vacuum aspiration with a Karman cannula, followed by sharp curettage, if necessary, under ultrasound guidance. The primary outcome was the success rate of the treatment protocol, defined as no further treatment required until the complete resolution of the cesarean scar ectopic pregnancy. Resolution of the cesarean scar ectopic pregnancy was evaluated based on decline of beta-hCG and the absence of residual gestational material in the endometrial cavity. Treatment failure was defined as the necessity for further treatment required until the complete resolution of the cesarean scar ectopic pregnancy. A sample size calculation indicated that 54 participants were required to test the hypothesis RESULTS: A total of 54 women were enrolled and randomized. Number of previous cesarean deliveries ranged from 1 to 3. Overall, 10 women received a third dose of methotrexate with 7 of 27 (25.9%) participants in the hysteroscopic resection group and 3 of 27 (11.1%) in the dilation and evacuation group. The success rate was 100% (27/27) in the hysteroscopic resection group and 81.5% (22/27) in the dilation and evacuation group (relative risk, 1.22; 95% confidence interval, 1.01-1.48). Additional procedures were required in 5 cases of the control group, namely 3 hysterectomies, 1 laparotomic uterine segmental resection, and 1 hysteroscopic resection. The length of stay in the hospital was 9.0±2.9 days in the intervention group and 10.0±3.5 days in the control group (mean difference, -1.00 days; 95% confidence interval, -2.71 to 0.71). No cases of admission to intensive care unit or maternal death were reported., Conclusion: Hysteroscopic resection was associated with an increased success rate in the treatment of cesarean scar ectopic pregnancy when compared with ultrasound-guided dilation and evacuation., (Copyright © 2023. Published by Elsevier Inc.)

Objective: To describe a feasible fertility preservation strategy in a woman with vaginal carcinoma., Design: Video case report demonstrating the diagnostic work-up and laparoscopic oocyte retrieval performed under regional anesthesia., Setting: University tertiary care hospital., Patient(s): A 35-year-old nulliparous woman presented with vaginal bleeding and foul-smelling vaginal discharge. After a comprehensive diagnostic work-up, a final diagnosis of squamous cell carcinoma of the vagina stage II (Federation International Obstetrics and Gynecology classification) was made. As per the patient's desire, before undergoing chemoradiotherapy, the patient underwent oocyte cryopreservation. Transvaginal retrieval of oocytes was not feasible because of stenosis of the vaginal introitus and the potential risk of intracavitary tumor cell spillage. Transabdominal ultrasound-guided oocyte retrieval was not possible because of the body's habitus., Intervention(s): The patient underwent ovarian stimulation for in vitro fertilization. To minimize estrogen levels, letrozole was used during controlled ovarian stimulation. Laparoscopic oocyte retrieval was performed under spinal anesthesia., Main Outcome Measure(s): Successful laparoscopic egg retrieval and cryopreservation in a woman with squamous cell carcinoma of the vagina., Result(s): A total follicular count of nine was estimated before the oocyte retrieval. Eight oocytes were retrieved at laparoscopy, and eight mature oocytes were successfully cryopreserved. No complications were encountered, and the patient was discharged on the same day of surgery., Conclusion(s): To our knowledge, this is the first published case of fertility preservation using the laparoscopic approach in a patient with vaginal cancer. Letrozole is a valuable strategy to reduce high estrogen in patients with gynecological cancer undergoing controlled ovarian stimulation. Laparoscopy oocyte retrieval, performed under regional anesthesia, can be performed in an ambulatory setting and should be considered an effective fertility preservation strategy in patients with large vaginal tumors., (Copyright © 2023. Published by Elsevier Inc.)

Ferroptosis, an iron-dependent form of cell death, and dysregulated microRNA (miRNA) expression correlate with colorectal cancer (CRC) development and progression. The tumor suppressor ability of miR-148a-3p has been reported for several cancers. Nevertheless, the role of miR-148a-3p in CRC remains largely undetermined. Here, we aim at investigating the molecular mechanisms and regulatory targets of miR-148a-3p in the CRC cell death mechanism(s). To this end, miR-148a-3p expression was evaluated in SW480 and SW620 cells and normal colon epithelial CCD 841 CoN cells with quantitative real-time polymerase chain reaction (qRT-PCR). Data reported a reduction of miR-148a-3p expression in SW480 and SW620 cells compared to non-tumor cells ( p < 0.05). Overexpression of miR-148a selectively inhibited CRC cell viability ( p < 0.001), while weakly affecting normal CCD 841 CoN cell survival ( p < 0.05). At the cellular level, miR-148a-3p mimics promoted apoptotic cell death via caspase-3 activation ( p < 0.001), accumulation of mitochondrial reactive oxygen species (ROS) ( p < 0.001), and membrane depolarization ( p < 0.001). Moreover, miR-148a-3p overexpression induced lipid peroxidation ( p < 0.01), GPX4 downregulation ( p < 0.01), and ferroptosis ( p < 0.01), as revealed by intracellular and mitochondrial iron accumulation and ACSL4/TFRC/Ferritin modulation. In addition, levels of SLC7A11 mRNA and protein, the cellular targets of miR-148a-3p predicted by bioinformatic tools, were suppressed by miR-148a-3p's overexpression. On the contrary, the downregulation of miR-148a-3p boosted SLC7A11 gene expression and suppressed ferroptosis. Together, these in vitro findings reveal that miR-148a-3p can function as a tumor suppressor in CRC by targeting SLC7A11 and activating ferroptosis, opening new perspectives for the rationale of therapeutic strategies through targeting the miR-148a-3p/SLC7A11 pathway.

Purpose: To assess the impact of preoperative endocervicoscopy on obstetric outcomes and complications in women undergoing LEEP for CIN2 + ., Methods: This was a retrospective cohort study carried out between October 2012 and April 2018. All women had undergone cervical length measurement at T0 (before LEEP), T1 (6 months after LEEP), and T2 (at 20 weeks of pregnancy) through transvaginal ultrasound examination after LEEP for CIN2 + . A total of 528 patients fulfilled our inclusion criteria and contributed to the final analysis: 288 had undergone endocervicoscopy before the excisional procedure (Group A), while the remaining 240 (Group B) did not., Results: Patients who did not undergo endocervicoscopy showed a greater amount of tissue excised at LEEP compared to those of Group A (6.7% vs 31.9% in Group A and B, p < 0.01, respectively). A statistically relevant difference was detected in the lesion margins involvement: negative in 93.8% in Group A compared to 65.6% in Group B. The cervicometry before the treatment resulted in similar between the two groups, while a statistically significant difference was noted after 6 months (37.5 ± 2.9 mm in Group A vs 35.1 ± 3.8 mm in Group B, p < 0.01) and at 20th week pregnancy (36.9 ± 5.3 mm in Group A vs 33.5 ± 5.6 mm in Group B, p < 0.01). The number of pregnancies after LEEP as well as the difference in the elapsed time (in months) did not result in a statistical significance between the two groups. The threatened preterm labor (TPL) and the threatened miscarriage showed a statistically significant difference in incidence between the two groups (4,2% and 4.2% in Group A vs 15.3% and 25% in Group B, p < 0.01, respectively)., Conclusion: Endocervicoscopy reduces the size of the LEEP sample and in particular its depth, saving healthy cervical tissue, and guarantees the total eradication of the lesion as the resection margins are negative in almost all cases, allowing for a reduction of the rate of TPL and threatened miscarriage in women with CIN2 + , especially with Type 2 or 3 cervical squamocolumnar junction (SCJ)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In the past, some pregnant women have been recommended to be in activity restriction because of the presumed increased risk of preterm birth due to the increased release of catecholamines, which might stimulate myometrial activity, during exercise and aerobic activity., Objective: This study aimed to test the hypothesis that in women with singleton pregnancy and arrested preterm labor, activity restriction would reduce the rate of preterm birth at <37 weeks of gestation., Study Design: This was a parallel-group nonblinded randomized trial conducted at a single center in Italy. Eligible patients were those with a diagnosis of arrested preterm labor, defined as not delivering after 48 hours of hospitalization for threatened preterm labor, with transvaginal ultrasound cervical length ≤25 mm, no other symptoms of possible uterine contractions, and cervical dilatation <3 cm at pelvic examination. Inclusion criteria were singleton pregnancies between 24 0/7 and 33 6/7 weeks of gestation. Participants were randomized in a 1:1 ratio to either activity restriction at the time of discharge or no activity restriction. Women in the intervention group were recommended activity restriction, defined as the following: pelvic rest, prohibition of sexual activity, and reduction of work and/or nonwork activity. The primary endpoint was preterm birth at <37 weeks of gestation., Results: A total of 120 participants were included in the trial; 60 patients were enrolled in the activity restriction group and 60 in the control group. Preterm birth at <37 weeks of gestation occurred in 15 of 60 women (25.0%) in the activity restriction group and 23 of 60 women (38.3%) in the control group (relative risk, 0.65; 95% confidence interval, 0.38-1.12). There was no significant between-group difference in the incidence of preterm birth at <32 weeks and in neonatal outcomes, but the trial was not powered for these outcomes., Conclusion: In singleton gestations with arrested preterm labor, activity restriction, including pelvic rest, prohibition of sexual activity, and reduction of work and/or nonwork activity, does not result in a lower rate of preterm birth at <37 weeks. Given the evidence on the lack of benefits, use of activity restriction in this population should be discouraged., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To describe a conservative laparoscopic treatment of an advanced case of interstitial pregnancy diagnosed in a woman at 14 weeks of gestational age., Design: A video case report with demonstration of diagnostic workup and laparoscopic management of rare subtypes of ectopic pregnancy., Setting: University tertiary care hospital., Patient(s): A 32-year-old nulliparous woman at 14 weeks of gestational age, presented with moderate abdominal pain. She reported a history of irregular periods; however, no risk factor for ectopic pregnancy was identified. The human chorionic gonadotropin level was 7,345 mIU/mL. Transvaginal ultrasound revealed an empty uterine cavity and a complex heterogeneous mass of 6 cm on the left cornual region. The myometrial thickness surrounding the gestational sac was 4 mm., Intervention(s): There were several critical strategies for this laparoscopic approach. To reduce intraoperative bleeding, the peritoneum was opened, the ureters were identified, and bulldog clamps were used to temporarily reduce uterine vascularization. An intramyometrial injection of vasopressin was performed. After the first cornuostomy attempt, we had to perform a cornual resection to achieve complete removal of the ectopic mass. Multilayer uterine sutures and anatomical restoration to prevent adhesion were then accomplished. Institutional review board approval was not required for this case report as per our institution's policy; patient consent was obtained for publication of the case., Main Outcome Measure(s): Description of laparoscopic management of huge interstitial pregnancy., Result(s): The overall operation time was 55 minutes, and the estimated blood loss was 55 mL. A successfully conservative treatment was achieved with no short-term complications. Postoperative ultrasound showed a normal uterus, and complete regression of human chorionic gonadotropin level was achieved 2 weeks after surgery., Conclusion(s): Interstitial ectopic pregnancy presents a high risk of maternal mortality considering that the interstitial part of the tube, because of its thickness, has a great capacity to expand before rupture. Despite the dimension of the lesion, in our case, the tube was still intact and the patient was in a stable clinical condition. Although cornuostomy is a more conservative solution, in these cases, cornual resection should be preferred. Through the accomplishment of reproducible key steps, laparoscopic removal of interstitial pregnancy is a feasible method and can be proposed even for advanced cases of interstitial pregnancies., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Acute pancreatitis (AP) is a potentially life-threatening illness characterized by an exacerbated inflammatory response with limited options for pharmacological treatment. Here, we describe the rational development of a library of soluble epoxide hydrolase (sEH) inhibitors for the treatment of AP. Synthesized compounds were screened in vitro for their sEH inhibitory potency and selectivity, and the results were rationalized by means of molecular modeling studies. The most potent compounds were studied in vitro for their pharmacokinetic profile, where compound 28 emerged as a promising lead. In fact, compound 28 demonstrated a remarkable in vivo efficacy in reducing the inflammatory damage in cerulein-induced AP in mice. Targeted metabololipidomic analysis further substantiated sEH inhibition as a molecular mechanism of the compound underlying anti-AP activity in vivo . Finally, pharmacokinetic assessment demonstrated a suitable profile of 28 in vivo . Collectively, compound 28 displays strong effectiveness as sEH inhibitor with potential for pharmacological AP treatment.

Canine mammary tumours (CMTs) are the most common cancer in intact female dogs. In addition to surgery, additional targeted and non-targeted therapies may offer survival benefits to these patients. Therefore, exploring new treatments for CMT is a promising area in veterinary oncology. CMT cells have an altered lipid metabolism and use the oxidation of fatty acids for their energy needs. Here we investigated the tumoricidal effects of teglicar, a reversible inhibitor of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme for fatty acid import into mitochondria, on two CMT cells, P114 and CMT-U229. Viability and apoptosis were examined in CMT cells using the crystal violet assay, trypan blue assay, and flow cytometry analysis. The expression of mediators of apoptosis signalling (e.g., caspase-9, caspase-8, and caspase-3) was assessed by quantitative real-time polymerase chain reaction and western blot analyses. Teglicar was able to decrease cell viability and induce apoptosis in P114 and CMT-U229 cells. At the molecular level, the effect of teglicar was associated with an upregulation of the mRNA expression levels of caspase-9 , caspase-8, and caspase-3 and an increase in their protein levels. In summary, our results show that teglicar has a potential effect against CMTs through the induction of apoptotic cell death, making it a promising therapeutic agent against CMTs.

Objective: To demonstrate the intraoperative use of three-dimensional (3D) imaging reconstruction for a complex case of multiple myomectomy assigned to robot-assisted laparoscopic surgery., Design: Stepwise demonstration of the technique with narrated video footage., Setting: University tertiary care hospital., Patient(s): A 36-year-old nulliparous infertile woman with multiple uterine myomas (>20) presented with menorrhagia and pelvic discomfort for many months. Because of the huge number of fibroids present, the patient was considered eligible for laparoscopic robotic-assisted myomectomy., Intervention(s): A robotic-assisted laparoscopic myomectomy was performed with the use of intraoperative 3D imaging reconstruction. After opening the retroperitoneum through the adnexal triangle and identifying the ureters, to reduce intraoperative bleeding, bulldog clamps were used to temporarily reduce uterine vascularization. A multiple myomectomy was then performed with the use of tenaculum and Maryland bipolar forceps. During the intervention, the surgeon used the 3D uterine reconstruction to adapt its surgical strategy. Multilayer running closure was achieved using a bidirectional barbed suture ensuring introflexion of the serosa. Patients' consent was obtained for publication of the case; institutional review board approval was not required for this case report as per our institution's policy., Main Outcome Measure(s): Description of a robotic-assisted myomectomy with the intraoperative use of 3D imaging reconstruction., Result(s): The total operative time was 105 minutes. A total of 21 fibroids were removed with 150 mL of intraoperative blood loss. The patient was discharged the day after., Conclusion(s): The application of 3D imaging technology could overcome one of the limitations of robot-assisted minimally invasive surgery, the lack of haptic feedback, enabling the surgeon to rapidly locate myomas and guide the intraoperative plan to optimize the results. Additional studies evaluating the clinical impact of this technique and its improvement are required., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Premna , a genus consisting of approximately 200 species, predominantly thrives in tropical and subtropical areas. Many of these species have been utilized in ethnopharmacology for diverse medicinal applications. In Saudi Arabia, Premna resinosa (Hochst.) Schauer (Lamiaceae) grows wildly, and its slightly viscid leaves are attributed to the production of leaf accession. In this study, we aimed to extract the surface accession from fresh leaves using dichloromethane to evaluate the anticancer potential. The plant exudate yielded two previously unknown labdane diterpenes, Premnaresone A and B, in addition to three already described congeners and four known flavonoids. The isolation process was accomplished using a combination of silica gel column chromatography and semi-preparative HPLC, the structures of which were identified by NMR and HRESIMS analyses and a comparison with the literature data of associated compounds. Furthermore, we employed a density functional theory (DFT)/NMR approach to suggest the relative configuration of different compounds. Consequently, we investigated the possibility of developing new chaperone inhibitors by subjecting diterpenes 1 - 5 to a Surface Plasmon Resonance-screening, based on the knowledge that oridonin, a diterpene, interacts with Heat Shock Protein 70 (Hsp70) 1A in cancer cells. Additionally, we studied the anti-proliferative activity of compounds 1 - 5 on human Jurkat (human T-cell lymphoma) and HeLa (epithelial carcinoma) cell lines, where diterpene 3 exhibited activity in Jurkat cell lines after 48 h, with an IC 50 of 15.21 ± 1.0 µM. Molecular docking and dynamic simulations revealed a robust interaction between compound 3 and Hsp70 key residues.

Objective: The surgical management of polycystic ovary syndrome (PCOS) represents an unclear option compared to medical therapy, and it is necessary to deepen the role of minimally invasive surgery, represented by laparoscopic ovarian drilling (LOD) and transvaginal hydrolaparoscopy (THL), for the treatment of PCOS in infertile women resistant to drug therapy and to establish its success in terms of ovulation and pregnancy rates., Methods: A search was performed in the main electronic databases (MEDLINE, EMBASE, Web of Science, PubMed, and the Cochrane Library) from 1994 to October 2022 in order to evaluate the role of surgery in patients with PCOS resistant to pharmacological treatment. Only original scientific articles in English were included., Results: Seventeen studies were analyzed in this review. In all analyzed studies, more than 50% of the population underwent spontaneous ovulation after surgical treatment without great differences between the two surgical techniques (LOD and THL). More than 40% of patients delivered, with a higher rate after LOD, although eight ectopic pregnancies and sixty-three miscarriages were reported. A lower risk of adhesion formation after THL has been reported. No clear data regarding the effect of surgery on the regularization of the menstrual cycle has been described. A reduction in LH and AMH serum levels as well as the LH/FSH ratio compared to preoperative levels for both surgical techniques has been described., Conclusions: Despite the scarcity and heterogeneity of data, surgical therapy could be considered an effective and safe approach in the management of PCOS patients with resistance to pharmacological treatment who desire to become pregnant.

Testicular ultrasonography and steroid concentrations (cortisol, dehydroepiandrosterone sulfate (DHEA-S), cortisol/DHEA-S ratio, testosterone) in hair were examined for their utility in the bull breeding soundness evaluation (BBSE). Beef and dairy bulls ( n = 16; 2.7 ± 0.4 years old; body condition score 3.2 ± 0.1) of five breeds were maintained under the same conditions at an accredited semen collection center. Bulls underwent routine semen collection twice weekly for 12 weeks and semen was processed and cryopreserved. Ultrasonography and hair sampling were undertaken at the last semen collection. Bulls with homogeneous testicular parenchyma ( n = 8) had a higher ( p < 0.05) percentage of motile sperm post-thawing compared with bulls with heterogeneous parenchyma ( n = 8). There were no differences ( p > 0.05) in the hair concentrations of cortisol, DHEA-S, and testosterone between bulls with homogeneous and heterogeneous parenchyma. In bulls with homogeneous parenchyma, hair DHEA-S concentration was positively correlated with percentage motile sperm (R 2 = 0.76), progressively motile sperm (R 2 = 0.70), and motility yield (R 2 = 0.71). The findings indicate that the integration of testicular ultrasonography and hair DHEA-S status in the BBSE could provide a more comprehensive assessment of indicative fertility in bulls. Additionally, ultrasonography can be used in the BBSE when the evaluation of semen parameters is not available.

The discovery of new bioactivities is closely related to the generation of novel scaffolds, and in the past few years different strategies have been proposed to obtain unknown architectures from the manipulation of known compounds. In the present study, we exploited a vintage photochemical approach for the discovery of an unexpected pathway of reactivity related to Δ 1 -3-oxo-pentacyclic triterpenic acids gaining access to a new class of natural-unnatural 5(10→1) abeo -pentacyclic triterpenic acids.

Adhesion formation following gynecological surgery remains a challenge. The adoption of minimally invasive surgical approaches, such as conventional or robotic-assisted laparoscopy combined with meticulous microsurgical principles and the application of adhesion-reducing substances, is able to reduce the risk of de novo adhesion formation but do not eliminate it entirely. Myomectomy is the most adhesiogenic surgical procedure and postoperative adhesions can have a significant impact on the ability to conceive. Therefore, when surgery is performed as infertility treatment, attention should be paid to whether the benefits outweigh the risks. Among several factors, the size and the location of fibroids are the most accountable factors in terms of adhesion development and post surgical infertility; therefore, the search for effective strategies against adhesion formation in this setting is of paramount importance. The purpose of this review is to evaluate the incidence and factors of adhesion formation and the best preventive measures current available., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Mercorio, Della Corte, Boccia, Palumbo, Reppuccia, Buonfantino, Cuomo, Borgo, Zitiello, De Angelis, Laganà, Bifulco and Giampaolino.)

The use of computational techniques in the early stages of drug discovery has recently experienced a boost, especially in the target identification step. Finding the biological partner(s) for new or existing synthetic and/or natural compounds by "wet" approaches may be challenging; therefore, preliminary in silico screening is even more recommended. After a brief overview of some of the most known target identification techniques, recent advances in structure-based computational approaches for target identification are reported in this digest, focusing on Inverse Virtual Screening and its recent applications. Moreover, future perspectives concerning the use of such methodologies, coupled or not with other approaches, are analyzed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

development of antibiotics, antineoplastics, and therapeutics for other diseases. Natural products are unique among all other small molecules in that they are produced by dedicated enzymatic assembly lines that are the protein products of biosynthetic gene clusters. As the products of chiral macromolecules, natural products have distinct three-dimensional shapes and stereochemistry is often encoded in their structures through the presence of stereocenters, or in the case of molecules that lack a stereocenter, the presence of an axis or plane of chirality. In the latter forms of chirality, if the barrier to rotation about the chiral axis or chiral plane is sufficiently high, stable conformers may exist allowing for isolation of discrete conformers, also known as atropisomers. Importantly, the diverse functions and biological activities of natural products are contingent upon their structures, stereochemistry and molecular shape. With continued innovation in methods for natural products discovery, synthetic chemistry, and analytical and computational tools, new insights into atropisomerism in natural products and related scaffolds are being made. As molecular complexity increases, more than one form of stereoisomerism may exist in a single compound (for example, point chirality, chiral axes, and chiral planes), sometimes creating atypical or noncanonical atropisomers, a term used to distinguish physically noninterconvertable atropisomers from typical atropisomers.Here we provide an account of the discovery and unusual structural and stereochemical features of the chrysophaentins, algal derived inhibitors of the bacterial cytoskeletal protein FtsZ and its associated protein partners. Eleven members of the chrysophaentin family have been discovered to date; seven of these are macrocyclic bis-bibenzyl ethers wherein the site of the ether linkage yields either a symmetrical or asymmetrical macrocyclic ring system. The asymmetrical ring system is highly strained and corresponds to the compounds having the most potent antimicrobial activity among the family. We review the structure elucidation and NMR properties that indicate restricted rotation between axes of two biaryl ethers, and the plane represented by the substituted 2- Z -butene bridge common to all of the macrocycles. Computational studies that corroborate high barriers to rotation about one representative plane, on the order of 20+ kcal/mol are presented. These barriers to rotation fix the conformation of the macrocycle into a bowl-like structure and suggest that an atropisomer should exist. Experimental evidence for atropisomerism is presented, consistent with computational predictions. These properties are discussed in the context of the total synthesis of 9-dechlorochrysophaenin A and its ring C isomers. Last, we discuss the implications for the presence of enantiomers in the biological activity and macrocyclization of the natural product.

Hereditary women's syndromes due to inherited mutations result in an elevated risk of developing gynecological cancers over the lifetime of affected carriers. The BRCA 1 and 2 mutations, Lynch syndrome (LS), and mutations in rare hereditary syndromes increase this risk and require more effective management of these patients based on surveillance and prophylactic surgery. Patients need counseling regarding risk-reducing surgery (RRS) and the time required to perform it, considering the adverse effects of premenopausal surgery and the hormonal effect on quality of life, bone density, sexual activity, and cardiological and vascular diseases. Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard for BRCA-mutated patients. An open question is that of endometrial cancer (EC) risk in patients with BRCA1/2 mutation to justify prophylactic hysterectomy during RRSO surgical procedures. RRS provides a 90-95% risk reduction for ovarian and breast cancer in women who are mutation carriers, but the role of prophylactic hysterectomy is underinvestigated in this setting of patients. In this review, we evaluate the management of the most common hereditary syndromes and the benefits of risk-reducing surgery, particularly exploring the role of prophylactic hysterectomy., Competing Interests: The authors declare no conflicts of interest.

The buffalo dairy sector is extending its boundaries to include new buffalo cheese productions beyond mozzarella, overcoming some barriers that make cheeses expensive and unsustainable. This study aimed to evaluate the effects of both the inclusion of green feed in the diet of Italian Mediterranean buffaloes and an innovative ripening system on buffalo cheese quality, providing solutions capable of guaranteeing the production of nutritionally competitive and sustainable products. For this purpose, chemical, rheological, and microbiological analyses were carried out on cheeses. Buffaloes were fed with or without the inclusion of green forage. Their milk was used to produce dry ricotta and semi-hard cheeses, ripened according to both respective traditional (MT) and innovative methods (MI); these are based on automatic adjustments of climatic recipe guided by the continuous control of pH. Green feed enhances the nutritional profile of the final products (high content of MUFAs and PUFAs). As far as the ripening method is concerned, to our knowledge, this is the first study that tests aging chambers, commonly used for meat, for the maturing of buffalo cheeses. Results pointed out the MI validity also in this field of application, as it shortens the ripening period without negatively compromising any of desirable physicochemical properties and the safety and hygiene of the final products. Conclusively, this research highlights the benefits of diets rich in green forage on productions and provides support for the ripening optimization of buffalo semi-hard cheeses.

Targeting bromodomain-containing protein 9 (BRD9) represents a promising strategy for the development of new agents endowed with anticancer properties. With this aim, a set of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based compounds was investigated following a combined approach that relied on in silico studies, chemical synthesis, biophysical and biological evaluation of the most promising items. The protocol was initially based on molecular docking experiments, accounting a library of 1896 potentially synthesizable items tested in silico against the bromodomain of BRD9. A first set of 21 compounds (1-21) was selected and the binding on BDR9 was assessed through AlphaScreen assays. The obtained results disclosed compounds 17 and 20 able to bind BRD9 in the submicromolar range (IC 50  = 0.35 ± 0.18 μM and IC 50  = 0.14 ± 0.03 μM, respectively) showing a promising selectivity profile when tested against further nine bromodomains. Taking advantage of 3D structure-based pharmacophore models, additional 10 derivatives were selected in silico for the synthetic step and binding assessment, highlighting seven compounds (22, 23, 25, 26, 28, 29, 31) able to selectively bind BRD9 among different bromodomains. The ability of the identified BRD9 binders to cross artificial membranes in vitro was also assessed, revealing a very good passive permeability profile. Preliminary studies were carried out on a panel of healthy and cancer human cell lines to explore the biological behavior of the selected compounds, disclosing a moderate activity and significant selectivity profile towards leukaemia cells. These results highlighted the applicability of the reported multidisciplinary approach for accelerating the selection of promising items and for driving the chemical synthesis of novel selective BRD9 binders. Moreover, the low molecular weight of the reported 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based BRD9 binders suggests the possibility for further exploring the chemical space in order to obtain new analogues with improved potency., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Since February 2020, the spread of Coronavirus Disease 2019 (COVID-19) in Italy has induced the government to call for lockdown of any activity apart from primary needs, and changing the lives of each of us. All that has dramatically impacted the management of patients affected by cancer. Patients with vulvar cancer (VC) represent a particularly frail population because they are elderly and affected by multiple comorbidities. The aim of this study is to evaluate the clinical impact of the SARS-CoV-2 infection on VC patients in terms of delay or impossibility of carrying out the scheduled treatment. Methods: The medical records of patients affected by vulvar tumors, referred to "DAI Materno-Infantile" of AOU Federico II of Naples between February 2020 and January 2022 were retrospectively analyzed. The presence of a positive reverse transcription-polymerase chain reaction (RT-PCR) in nasopharyngeal swab defined the positivity to SARS-CoV-2. Results: Twenty-four patients with VC were analyzed and scheduled for treatment. The median age was 70.7 years (range: 59-80). Seven (29.2%) patients were diagnosed with SARS-CoV-2 infection: In three (42.8%) patients, the treatment was delayed with no apparent consequences, in four (57.2%), the treatment was delayed or changed due to cancer progression and, of these four, one died due to respiratory complications of COVID-19, and one died due to oncologic disease progression. Conclusion: COVID-19 caused, in most cases, significant delays in oncologic treatments and high mortality in our series of patients affected by VC.

Wet-aging (WA) and dry-aging (DA) methods are usually used in the beef industry to satisfy the consumers' tastes; however, these methods are not suitable for all anatomical cuts. In this study, WA and DA were applied to improve the quality of two cuts of Charolais beef ( Longissimus dorsi and Semitendinosus ). For 60 days (i.e., 2 days, 15 days, 30 days and 60 days of sampling), a physicochemical, rheological, and microbiological analysis were performed at WA (vacuum packed; temperature of 4 ± 1 °C) and at DA (air velocity of 0.5 m/s; temperature of 1 ± 1 °C; relative humidity of 78 ± 10%) conditions. The results showed that the aging method influenced the aging loss (higher in the DA), cooking loss (higher in the WA), malondialdehyde concentration (higher in the DA) and fatty acid profile (few changes). No differences in the drip loss and color were observed, which decreased after 30 days of aging. The WBSF and TPA test values changed with increasing an aging time showing that the aging improved the tenderness of meat regardless of the aging method. Moreover, the aging method does not influence the microbiological profile. In conclusion, both WA and DA enhanced the quality of the different beef cuts, suggesting that an optimal method-time and aging combination could be pursued to reach the consumers' preferences.

Despite wide screening campaigns and early detection, cervical cancer remains the fourth most common cancer among women. Radical hysterectomy, whether by open, laparoscopic or by robotic-assisted techniques, is the mainstay treatment. However, for adequate surgical results and good oncological prognosis, a gynecological surgeon should be trained to perform those procedures. The learning curve of radical hysterectomy, especially by laparoscopy, is influenced by several factors. The LACC trial, the decrease in cervical cancer incidence and radical hysterectomy procedures have widely reduced the learning curve for surgeons. This article mainly discusses the learning curve of laparoscopic radical hysterectomy for cervical cancers, and how several factors are influencing it negatively, with the need to have medical authorities reset specific surgical training programs and allocate them to special oncological centers.

Background and Objectives: The standard treatment approach in locally advanced cervical cancer (LACC) is exclusive concurrent chemoradiation therapy (RTCT). The risk of local residual disease after six months from RTCT is about 20-30%. It is directly related to relapse risk and poor survival, such as in patients with recurrent cervical cancer. This systematic review aims to describe studies investigating salvage surgery's role in persistent/recurrent disease in LACC patients who underwent definitive RTCT. Materials and Methods: Studies were eligible for inclusion when patients had LACC with radiologically suspected or histologically confirmed residual disease after definitive RTCT, diagnosed with post-treatment radiological workup or biopsy. Information on complications after salvage surgery and survival outcomes had to be reported. The methodological quality of the articles was independently assessed by two researchers with the Newcastle-Ottawa scale. Following the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we systematically searched the PubMed, Scopus, Cochrane, Medline, and Medscape databases in May 2022. We applied no language or geographical restrictions but considered only English studies. We included studies containing data about postoperative complications and survival outcomes. Results: Eleven studies fulfilled the inclusion criteria and all were retrospective observational studies. A total of 601 patients were analyzed concerning the salvage surgery in LACC patients for persistent/recurrent disease after RTCT treatment. Overall, 369 (61.4%) and 232 (38.6%) patients underwent a salvage hysterectomy (extrafascial or radical) and pelvic exenteration (anterior, posterior, or total), respectively. Four hundred and thirty-nine (73%) patients had histologically confirmed the residual disease in the salvage surgical specimen, and 109 patients had positive margins (overall range 0-43% of the patients). The risk of severe (grade ≥ 3) postoperative complications after salvage surgery is 29.8% (range 5-57.5%). After a median follow-up of 38 months, the overall RR was about 32% with an overall death rate of 40% after hysterectomy or pelvic exenteration with or without lymphadenectomy. Conclusions: There is heterogeneity between the studies both in their design and results, therefore the effect of salvage surgery on survival and recurrence cannot be adequately estimated. Future homogeneous studies with an appropriately selected population are needed to analyze the safety and efficacy of salvage hysterectomy or pelvic exenteration in patients with residual tumors after definitive RTCT.

Scabiosa atropurpurea L. subsp. maritima (L.) Arc. (Caprifoliaceae) is a plant widely distributed in the Mediterranean region and represented by 32 taxa in the flora of Turkey. In the present study, an in-depth phytochemical investigation of S. atropurpurea methanol extract of the whole plant was carried out using a combination of LC-ESI-FT-MS and NMR analysis. This approach allowed the isolation and structural elucidation of 28 compounds: 17 iridoids, 7 flavonoids, and 4 phenolic acids. Among these compounds, three previously unreported iridoids named secologanin-methyl-hemiacetal, atropurpurin A, and atropurpurin B were identified. The methanol extract of S. atropurpurea was assayed for its antioxidant and antihyperglycemic activity, showing a potent α-glucosidase inhibitory activity (IC 50  = 100 μg/mL), higher than that exerted by acarbose (IC 50  = 196 μg/mL), used as the positive control. Thus, the most abundant iridoids were selected to be tested for their antihyperglycemic activity, and molecular docking experiments were carried out to assess the possibility for selected compounds to form complexes with α-glucosidase enzyme active site., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Vulvar Paget's disease (VPD) is defined as a neoplasm of epithelial origin, mostly in postmenopausal women. Due to the extreme rarity of VPD, limited data about recommended treatment options are available. Surgical excision has been the treatment of choice although in the recent decade medical treatments have been proposed., Methods: A systematic computerized search of the literature was performed in the main electronic databases (MEDLINE, EMBASE, Web of Science, PubMed, and Cochrane Library), from 2003 to September 2022, in order to analyze all medical and surgical strategies used for the treatment of VPD., Results: Thirty-four articles were included in this review with findings as follows: 390 patients were treated with medical or other conservative treatment while 2802 patients were treated surgically; 235/434 (54%) patients had a complete response, 67/434 (15%) a partial response, 10/434 (2.3%) a stable disease, 3/434 (0.7%) disease progress, 3/434 (0.7%) died of the disease, 55/434 (13%) died of other causes during follow up while 7/434 (1.6%) had to stop topical treatments with 5% imiquimod cream because of side effects; 239/434 patients (55%) had a recurrence and 11/434 (2.5%) were lost to follow-up. The length of follow-up was variable, according to the different studies analyzed., Conclusion: VPD is a chronic disease with a high recurrence rate and low mortality. There are no significant differences in recurrence rates in patients who undergo surgery and those who do not and the margin status at the time of primary surgery and recurrence. Several surgical and medical approaches providing both local control of the disease and minimal tissue damage have been developed. Clock mapping, a recent preoperative vulvo-vaginal workup tool, can predict the invasiveness and the extension of VPD. However, to date, due to the different treatment options available and in the absence of a global consensus, it is critical to tailor treatments to individual patient characteristics and biopsy histopathologic findings, to ensure the best type of therapy.

Different molecular mechanisms contribute to the development of multidrug resistance in cancer, including increased drug efflux, enhanced cellular repair mechanisms and alterations of drug metabolism or drug targets. ABCG2 is a member of the ATP-binding cassette superfamily transporters that promotes drug efflux, inducing chemotherapeutic resistance in malignant cells. In this context, the development of selective ABCG2 inhibitors might be a suitable strategy to improve chemotherapy efficacy. Thus, through a multidisciplinary approach, we identified a new ABCG2 selective inhibitor ( 8 ), highlighting its ability to increase mitoxantrone cytotoxicity in both hepatocellular carcinoma (EC 50 from 8.67 ± 2.65 to 1.25 ± 0.80 μM) and transfected breast cancer cell lines (EC 50 from 9.92 ± 2.32 to 2.45 ± 1.40 μM). Moreover, mitoxantrone co-administration in both transfected and non-transfected HEK293 revealed that compound 8 notably lowered the mitoxantrone EC 50, demonstrating its efficacy along with the importance of the ABCG2 extrusion pump overexpression in MDR reversion. These results were corroborated by evaluating the effect of inhibitor 8 on mitoxantrone cell uptake in multicellular tumor spheroids and via proteomic experiments.

Although vaccines are greatly mitigating the worldwide pandemic diffusion of SARS-Cov-2, therapeutics should provide many distinct advantages as complementary approach to control the viral spreading. Here, we report the development of new tripeptide derivatives of AT1001 against SARS-CoV-2 M pro . By molecular modeling, a small compound library was rationally designed and filtered for enzymatic inhibition through FRET assay, leading to the identification of compound 4. X-ray crystallography studies provide insights into its binding mode and confirm the formation of a covalent bond with M pro C145. In vitro antiviral tests indicate the improvement of biological activity of 4 respect to AT1001. In silico and X-ray crystallography analysis led to 58, showing a promising activity against three SARS-CoV-2 variants and a valuable safety in Vero cells and human embryonic lung fibroblasts. The drug tolerance was also confirmed by in vivo studies, along with pharmacokinetics evaluation. In summary, 58 could pave the way to develop a clinical candidate for intranasal administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The application of a multi-step scientific workflow revealed an unprecedented class of PGE 2 /leukotriene biosynthesis inhibitors with in vivo activity. Specifically, starting from a combinatorial virtual library of ∼4.2 × 10 5 molecules, a small set of compounds was identified for the synthesis. Among these, four novel 2-aminoacyl-1,3,4-thiadiazole derivatives ( 3 , 6 , 7 , and 9 ) displayed marked anti-inflammatory properties in vitro by strongly inhibiting PGE 2 biosynthesis, with IC 50 values in the nanomolar range. The hit compounds also efficiently interfered with leukotriene biosynthesis in cell-based systems and modulated IL-6 and PGE 2 biosynthesis in a lipopolysaccharide-stimulated J774A.1 macrophage cell line. The most promising compound 3 showed prominent in vivo anti-inflammatory activity in a mouse model, with efficacy comparable to that of dexamethasone, attenuating zymosan-induced leukocyte migration in mouse peritoneum with considerable modulation of the levels of typical pro-/anti-inflammatory cytokines., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

A deep in silico investigation of various microsomal prostaglandin E 2 synthase-1 (mPGES-1) protein systems is here reported using molecular dynamics (MD) simulations. Firstly, eight different proteins models (Models A-H) were built, starting from the active enzyme trimer system (Model A), namely that bound to three glutathione (GSH) cofactor molecules, and then gradually removing the GSHs (Models B-H), simulating each of them for 100 ns in explicit solvent. The analysis of the obtained data disclosed the structural role of GSH in the chemical architecture of mPGES-1 enzyme, thus suggesting the unlikely displacement of this cofactor, in accordance with experimentally determined protein structures co-complexed with small molecule inhibitors. Afterwards, Model A was submitted to microsecond-scale molecular dynamics simulation (total simulation time=10 μs), in order to shed light about the dynamical behaviour of this enzyme at atomic level and to obtain further structural features and protein function information. We confirmed the structural stability of the enzyme machinery, observing a conformational rigidity of the protein, with a backbone RMSD of ∼3 Å along the simulation time, and highlighting the strong active contribution of GSH molecules due to their active role in packing the protein chains through a tight binding at monomer interfaces. Furthermore, the focused analysis on R73 residue disclosed its role in solvent exchange events, probably excluding its function as route for GSH to enter towards the endoplasmic reticulum membrane, in line with the recently reported function of cap domain residues F44-D66 as gatekeeper for GSH entrance into catalytic site., (© 2022 The Authors. Molecular Informatics published by Wiley-VCH GmbH.)

Purpose: Regional anesthesia (RA) is considered as a "minimally invasive technique" to achieve anesthesia. To assess the feasibility and the perioperative outcomes of laparoscopic hysterectomy in regional anesthesia from the point of view of the surgeon, anesthesiologist and patient., Methods: A retrospective search was performed to identify patients who underwent laparoscopic hysterectomy under RA from April 2020 to September 2021. Five patients affected by benign gynecological disease (atypical endometrial hyperplasia or uterine leiomyomas) were included., Results: The postoperative pain, nausea, and vomiting (PONV) and the antiemetic/analgesic intake were evaluated. Postoperative surgical and anesthesiological variables were recorded. Duration of surgery was 84 ± 4.18 and no conversion to GA was required. According to VAS score, the postoperative pain during the whole observation time was less than 4 (median). A faster resumption of bowel motility (≤ 9 h) and patient's mobilization (≤ 4 h) were observed as well as a low incidence of post-operative nausea and vomit. Early discharge and greater patient's satisfaction were recorded. Intraoperatively pain score was assessed on Likert scale during all the stages of laparoscopy in RA, with only 2 patients complaining scarce pain (= 2) at pneumoperitoneum., Conclusion: RA showed to have a great impact on surgical stress and to guarantee a quicker recovery without compromising surgical results. RA technique could be a viable option for patients undergoing laparoscopic hysterectomy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The optimal gestational age at delivery for stable women with suspected placenta accreta is still subject of debate., Objective: To estimate the likelihood of vaginal bleeding necessitating expedited delivery in women with placenta accreta according to gestational age at planned cesarean hysterectomy., Study Design: This was a multicenter cohort study. Singleton pregnancies at risk of placenta accreta because of placenta previa in the setting of prior cesarean delivery were included. Outcomes were compared in cohort of women who had planned cesarean hysterectomy at 34 0/7 - 34 6/7 weeks versus at 35 0/7 - 35 6/7 weeks. The primary outcome was incidence of vaginal bleeding severe enough to necessitate delivery., Results: 118 singleton pregnancies with placenta previa in the setting of prior cesarean delivery, and confirmed placenta accreta at the time of delivery were included in the study. Women who had planned cesarean hysterectomy at 34 weeks had lower episodes of vaginal bleeding severe enough to necessitate immediate or emergency delivery (20.6% vs 38.0%; odds ratio (OR) 0.42, 95% confidence interval (CI) 0.19 to 0.96). Eight women (11.8%) in the 34 weeks group and 6 women (12.0%) in the 35 weeks group delivered before the planned date due to onset of spontaneous labor (OR 0.98, 95% CI 0.32 to 3.02)., Conclusion: In singleton gestations with suspected placenta accreta, planned cesarean hysterectomy at 34 0/7 - 34 6/7 weeks was associated with a decreased chance of unscheduled delivery due to severe vaginal bleeding., Condensation: In case of placenta accreta, planned cesarean hysterectomy at 34 weeks was associated with decreased chance of unscheduled delivery due to severe vaginal bleeding.

The aim of this study was, firstly, to analyze the histopathological characteristics of placentas in women with uneventful pregnancies and affected by COVID-19 at the time of delivery; and secondly, to correlate histological findings to maternal and neonatal characteristics. In our single-center prospective observational study, 46 placentas from term uncomplicated singleton pregnancies of patients with a documented SARS-CoV-2 infection at the time of delivery underwent histological examination. Despite a normal feto-maternal outcome, most of the placentas (82.6%) presented signs of maternal vascular malperfusion, while features of fetal vascular malperfusion were found in 54% of cases. No correlation was detected between maternal and neonatal characteristics and the severity of blood circulation disease, and abnormal findings were also described in asymptomatic patients. Moreover, we did not find any maternal symptoms or clinical details allowing for the prediction of abnormal placental findings in pregnancy complicated by COVID-19 infection. Our results suggest that SARS-CoV-2 infection during pregnancy could lead to acute placental dysfunction.

We identified 2,4-dinitro-biphenyl-based compounds as new inhibitors of leukotriene C 4 synthase (LTC 4 S) and 5-lipoxygenase-activating protein (FLAP), both members of the "Membrane Associated Proteins in Eicosanoid and Glutathione metabolism" (MAPEG) family involved in the biosynthesis of pro-inflammatory eicosanoids. By molecular docking we evaluated the putative binding against the targets of interest, and by applying cell-free and cell-based assays we assessed the inhibition of LTC 4 S and FLAP by the small molecules at low micromolar concentrations. The present results integrate the previously observed inhibitory profile of the tested compounds against another MAPEG member, i. e., microsomal prostaglandin E 2 synthase (mPGES)-1, suggesting that the 2,4-dinitro-biphenyl scaffold is a suitable molecular platform for a multitargeting approach to modulate pro-inflammatory mediators in inflammation and cancer treatment., (© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). In silico analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors. Enzymatic and cellular assays revealed the indoline derivative 43 as a notable 5-LOX inhibitor, guiding the design of new analogues. These compounds underwent extensive in vitro investigation revealing dual 5-LOX/sEH inhibitors, with 73 showing the most promising activity (IC 50 s of 0.41 ± 0.01 and 0.43 ± 0.10 μM for 5-LOX and sEH, respectively). When challenged in vivo in zymosan-induced peritonitis and experimental asthma in mice, compound 73 showed remarkable anti-inflammatory efficacy. These results pave the way for the rational design of 5-LOX/sEH dual inhibitors and for further investigation of their potential use as anti-inflammatory agents.

Primiparous buffaloes were tested in two periods of the year characterized, by either low or high reproductive efficiency. They were subjected to two protocols for synchronization of ovulation: (i) Ovsynch (OV) and (ii) progesterone based (P 4 ) treatment. After calving, the animals underwent a series of four cycles of re-synchronization protocols. The season did not affect pregnancy rates when the results of the two treatments were pooled together with regard to the first synchronization protocol, followed by AI. Pregnancy rates were similar during the low breeding season (50.3% vs. 57.4% in OV and P 4 , respectively), but different during the high breeding season (50.4% vs. 67.7% in OV and P 4 , respectively; p = 0.000). Logistic regression confirmed a significant effect of treatment and season interaction on pregnancy ( p = 0.003). Following re-synchronization, a treatment by season interaction was detected during the low breeding season (odds ratio = 2.233), in favor of P 4 . Finally, a survival analysis showed a better response of animals subjected to P 4 treatment from the second AI onward. In conclusion, the pooled data of pregnancy rates from both treatments between seasons are not different following AIs. Better results, though, were obtained from the implementation of P 4 treatment, and are recorded in a season-fashioned mode when the comparison is made following first or cumulative AIs.

Background: Since there is no available data on temporal trends of caesarean section (CS) rates in pregnant women with COVID-19 through the pandemic, we aimed to analyze the trends in caesarean section rate in a large cohort of pregnant women with COVID-19, according to the Robson Ten Group Classification System of deliveries., Methods: We prospectively enrolled pregnant women with a diagnosis of COVID-19 who delivered in our center between March 2020 and November 2021. Deliveries were classified, according to the Robson group classification, and according to three time periods: (1) deliveries from March 2020 to December 2020; (2) deliveries from January 2021 to April 2021; (3) deliveries from May 2021 to November 2021. We compared pregnancy characteristics and incidence of caesarean section, according to the Robson category in the total population, and according to the three time periods., Results: We included 457 patients matching the inclusion criteria in our analysis. We found that overall CS rate significantly decreased over time from period 1 to period 3 (152/222, 68.5% vs. 81/134, 60.4% vs. 58/101, 57.4%, χ 2 = 4.261, p = 0.039). CS rate significantly decreased over time in Robson category 1 (48/80, 60% vs. 27/47,57.4% vs. 8/24, 33.3%, χ 2 = 4.097, p = 0.043) and Robson category 3 (13/42, 31% vs. 6/33, 18.2% vs. 2/22, 9.1%, χ 2 = 4.335, p = 0.037). We also found that the incidence of induction of labor significantly increased over time (8/222, 3.6% vs. 12/134, 9% vs. 11/101, 10.9%, χ 2 = 7.245, p = 0.027)., Conclusion: Our data provide an overview of the temporal changes in the management and obstetric outcome of COVID-19 pregnant women through the pandemic, confirming that standards of obstetrical assistance for pregnancies complicated by SARS-CoV-2 infection improved over time.

The laparoscopic approach for the treatment of uterine leiomyoma is increasingly practiced. The necessity to remove large specimens from the small laparoscopic incision has always been one of the main limits of this procedure. The unrestricted use of morcellation, to overtake this weak point of minimally invasive surgery, has opened in recent years a broad debate, especially on the risk of unintended dissemination of cells that could in some cases lead to extremely negative repercussions. This review analyzes these aspects and the principal recommendations from the major gynecological society on this topic surveying their effects. Furthermore, the purpose of this article is to provide an overview of the different morcellation techniques and how they are performed, evaluating their advantages and disadvantages. Contained morcellation seems to overcome many limits; however, based on recent data, an appropriate evaluation and selection of patients, as well as complete counseling before the surgery, are mandatory.

The purpose of this study is to assess the feasibility and the perioperative outcomes of laparoscopic gynecological surgery in regional anesthesia (RA) from the point of view of the surgeon, anesthesiologist and patient. This is a prospective cohort study comprising sixty-six women planned to undergo gynecologic laparoscopy surgery for benign pathology at tertiary care gynecolgical center of the University Federico II of Naples. Women were assigned, according to their preference, to either RA (Group A) or general anesthesia (GA) (Group B). Surgical, anesthesiologic and postoperative recovery data were recorded. Postoperative pain was considered as the primary outcome. Secondary outcomes included mobilization, length of hospital stay, global surgeons and patient satisfaction, intraoperative pain assessment in Group A. Immediate postoperative pain was significantly lower in Group A 0 vs 2 (p < 0.001), with no significant differences at 24 h. The secondary outcome demonstrated early patient's mobilization (p < 0.001) as well as early discharge (p < 0.001) and greater patient's satisfaction for the Group A. In these patients, a maximum pain score of 3 points out of 5 was recorded through the entire surgery. RA showed to decrease the impact of surgical stress and to guarantee a quicker recovery without compromising surgical results. Although several surgical approaches can be employed to treat different conditions, RA technique could be a viable option for well-selected patients affected by gynecological diseases., (© 2022. The Author(s).)

Background: Endometrial cancer (EC) is one of the most common gynecologic malignancy, mostly in postmenopausal women. The gold standard treatment for EC is surgery, but in the early stages, it is possible to opt for conservative treatment. In the last decade, different clinical and pathological markers have been studied to identify women who respond to conservative treatment. A lot of immunohistochemical markers have been evaluated to predict response to progestin treatment, even if their usefulness is still unclear; the prognosis of this neoplasm depends on tumor stage, and a specific therapeutic protocol is set according to the stage of the disease., Objective: (1) To provide an overview of the conservative management of Stage 1A Grade (G) 2 endometrioid EC (FIGO) and the oncological and reproductive outcomes related; (2) to describe the molecular alterations before and after progestin therapy in patients undergoing conservative treatment., Materials and Methods: A systematic computerized search of the literature was performed in the main electronic databases (MEDLINE, Embase, Web of Science, PubMed, and Cochrane Library), from 2010 to September 2021, in order to evaluate the oncological and reproductive outcomes in patients with G2 stage IA EC who ask for fertility-sparing treatment. The expression of several immunohistochemical markers was evaluated in pretreatment phase and during the follow-up in relation to response to hormonal therapy. Only scientific publications in English were included. The risk of bias assessment was performed. Review authors' judgments were categorized as "low risk," "high risk," or "unclear risk" of bias., Results: Twelve articles were included in the study: 7 observational studies and 5 case series/reports. Eighty-four patients who took progestins (megestrol acetate, medroxyprogesterone acetate, and/or levonorgestrel-releasing intrauterine devices) were analyzed. The publication bias analysis turned out to be "low." 54/84 patients had a complete response, 23/84 patients underwent radical surgery, and 20/84 had a relapse after conservative treatment. Twenty-two patients had a pregnancy. The length of follow-up was variable, from 6 to 142 months according to the different studies analyzed. Several clinical and pathological markers have been studied to identify women who do not respond to conservative treatment: PR and ER were the most studied predictive markers, in particular PR appeared as the most promising; MMR, SPAG9, Ki67, and Nrf2-survivin pathway provided good results with a significant association with a good response to progestin therapy. However, no reliable predictive markers are currently available to be used in clinical practice., Conclusions: The conservative treatment may be an option for patients with stage IA G2 EEC who desire to preserve their fertility. The immunohistochemical markers evaluation looks promising in predicting response to conservative treatment. Further large series and randomized clinical trials are needed to confirm these results., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Pierluigi Giampaolino et al.)

In the present study, we aimed at assessing the influence of breed and feeding system on the bovine milk profile of betaines and carnitines and milk capacity in counteracting the inflammatory endothelial cell (EC) damage induced by interleukin (IL)-6. In the first experimental design, two breeds were chosen (Holstein vs. Modicana) to investigate the biomolecule content and antioxidant capacity in milk and dairy products. In the second experimental design, two feeding systems (pasture vs. total mixed ratio) were tested only in Holstein to evaluate the possible effect on the functional profile of milk and dairy products. Finally, the bulk milk from the two experimental designs was used to evaluate the efficacy of preventing IL-6-induced endothelial inflammatory damage. Results showed that Modicana milk and whey had higher biomolecule content and antioxidant activity compared to Holstein milk (p < 0.01). Milk from Holstein fed TMR showed higher concentration of γ-butyrobetaine, δ-valerobetaine (p < 0.01), and l-carnitine (p < 0.05). Similarly, whey from Holstein fed TMR also showed higher content of δ-valerobetaine, glycine betaine, l-carnitine, and acetyl-l-carnitine (p < 0.01) compared to the Holstein fed pasture. Conversely, the antioxidant activity of milk and dairy products was not affected by the feeding system. In ECs, all milk samples reduced the IL-6-induced cytokine release, as well as the accumulation of reactive oxygen species (ROS) and the induction of cell death, with the most robust effect elicited by Modicana milk (p < 0.01). Overall, Modicana milk showed a higher content of biomolecules and antioxidant activity compared to Holstein, suggesting that the breed, more than the feeding system, can positively affect the health-promoting profile of dairy cattle milk.