Properties of Configurationally Stable Atropoenantiomers in Macrocyclic Natural Products and the Chrysophaentin Family.

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.

Assessing ovarian stimulation with letrozole and levonorgestrel intrauterine system after combined fertility-sparing approach for atypical endometrial lesions: a retrospective case-control study.

RESEARCH QUESTION: Is ovarian stimulation with levonorgestrel intrauterine system (LNG-IUS) in situ and co-treatment with letrozole safe and effective in patients undergoing fertility-sparing combined treatment for atypical endometrial hyperplasia (AEH) or early endometrial cancer limited to the endometrium? DESIGN: Retrospective case-control study recruiting women who had undergone fertility-sparing 'combined' treatment and ovarian stimulation with letrozole and LNG-IUS in situ. The 'three steps' hysteroscopic technique was used. Once complete response was achieved, the ovaries were stimulated, and mature oocytes cryopreserved. The LNG-IUS was removed, and embryos transferred. A comparative analysis was conducted between the two control groups of the initial outcomes of ART (number of oocytes and MII oocytes retrieved): healthy infertile women undergoing ovarian stimulation for IVF/ICSI (control group A); and patients diagnosed with breast cancer who underwent ovarian stimulation with letrozole (control group B). RESULTS: Of the 75 patients analysed, 15 underwent oocyte cryopreservation after achieving a complete response to fertility-sparing treatment (study group); 30 patients in control group A and B, respectively. No statistically significant differences were observed in retrieved oocytes and mature oocytes between the study and control groups. In the nine patients who underwent embryo transfer, clinical pregnancy (55.6%), cumulative live birth (44.4%) and miscarriage (20%) rates were reported. In three patients with AEH, recurrence occurred (12%) at 3, 6 and 16 months after removing the LNG-IUS to attempt embryo transfer, respectively. CONCLUSION: Fertility-sparing hysteroscopic combined treatment and subsequent ovarian stimulation with letrozole and LNG-IUS in situ could be suggested to women with AEH or early endometrial cancer who ask for future fertility preservation.

PharmaCore: The Automatic Generation of 3D Structure-Based Pharmacophore Models from Protein/Ligand Complexes.

In this work, we present PharmaCore: a new, completely automatic workflow aimed at generating three-dimensional (3D) structure-based pharmacophore models toward any target of interest. The proposed approach relies on using cocrystallized ligands to create the input files for generating the pharmacophore hypotheses, integrating not only the three-dimensional structural information on the ligand but also data concerning the binding mode of these molecules put in the protein cavity. We developed a Python library that, starting from the specific UniProt ID of the protein under investigation as the only element that requires user intervention, subsequently collects and aligns the corresponding structures bearing a known ligand in a fully automated fashion, bringing them all into the same coordinate system. The protocol includes a final phase in which the aligned small molecules are used to produce the pharmacophore hypotheses directly onto the protein structure using a specific software, e.g., Phase (Schrödinger LLC). To validate the entire procedure and highlight the possible applications in the field of drug discovery and repositioning, we first generated pharmacophores for soluble epoxide hydrolase (sEH) and compared with already-published ones. Then, we reproduced the binding profile of a reported selective binder of ATAD2 bromodomain (AM879), testing it against a panel of 1741 pharmacophores related to 16 epigenetic proteins and automatically generated with PharmaCore, finally disclosing putative unprecedented off-targets. The computational predictions were successfully validated with AlphaScreen assays, highlighting the applicability of the proposed workflow in drug discovery and repositioning. Finally, the process was also validated on tankyrase 2 and SARS-CoV-2 MPro, confirming the robustness of PharmaCore.

3D Imaging reconstruction and laparoscopic robotic surgery approach to disseminated peritoneal leiomyomatosis.

OBJECTIVES: This video article explores the synergistic approach of 3D imaging reconstruction and laparoscopic robotic surgery for the management of a complex case of disseminated peritoneal leiomyomatosis (1). The primary focus lies in the capability of the reconstruction model to provide diagnostic support to identify fibroids during surgical procedures, potentially enhancing surgical precision, reducing operating times, minimizing uterine incisions, and limiting blood loss. 3D imaging reconstruction techniques were used to facilitate the identification of multiple parasitic and non-serosal myomas, which is particularly challenging when operating with a robotic surgical platform that lacks haptic feedback. SETTING: Tertiary referral center. PARTICIPANTS: A case report design was employed, focusing on a 43-year-old nulliparous infertile woman with multiple symptomatic uterine myomas. Our institution has made a further diagnosis of disseminated peritoneal leiomyomatosis(4-5). INTERVENTIONS: Due to the widespread nature of peritoneal leiomyomatosis and numerous uterine fibroids, robotic surgery was considered a preferable option based on our experience to operate within confined anatomical spaces. 3D imaging reconstruction technology was utilized for preoperative and intraoperative planning, enabling precise determination of the fibroids' location, size, and volume obtained through MRI imaging. Real-time 3D imaging guided rapid myoma localization and surgical strategy adjustment (2-3). The procedure resulted in the removal of 15 fibroids, with minimal blood loss (250 mL) and a total operative time of 120 minutes. Multilayer running hysterorraphy was performed using a barbed monofilament suture to ensure effective hemostasis, incorporating serosal introflection to reduce the risk of post-operative adhesion development. CONCLUSIONS: The combined approach of 3D imaging reconstruction and laparoscopic robotic surgery holds significant potential for the management of disseminated peritoneal leiomyomatosis. This approach can overcome some robotic surgery limitations, particularly the absence of haptic feedback, providing accurate preoperative planning and real-time intraoperative guidance, facilitating efficient fibroid localization, minimizing uterine incisions, and reducing blood loss. Further research is needed to fully evaluate the clinical impact of this promising technology.

Chemoproteomics Reveals USP5 (Ubiquitin Carboxyl-Terminal Hydrolase 5) as Promising Target of the Marine Polyketide Gracilioether A.

Mass spectrometry-based chemical proteomic approaches using limited proteolysis have become a powerful tool for the identification and analysis of the interactions between a small molecule (SM) and its protein target(s). Gracilioether A (GeA) is a polyketide isolated from a marine sponge, for which we aimed to trace the interactome using this strategy. DARTS (Drug Affinity Responsive Target Stability) and t-LiP-MS (targeted-Limited Proteolysis-Mass Spectrometry) represented the main techniques used in this study. DARTS was applied on HeLa cell lysate for the identification of the GeA target proteins, and t-LiP-MS was employed to investigate the protein's regions involved in the binding with GeA. The results were complemented through the use of binding studies using Surface Plasmon Resonance (SPR) and in silico molecular docking experiments. Ubiquitin carboxyl-terminal hydrolase 5 (USP5) was identified as a promising target of GeA, and the interaction profile of the USP5-GeA complex was explained. USP5 is an enzyme involved in the pathway of protein metabolism through the disassembly of the polyubiquitin chains on degraded proteins into ubiquitin monomers. This activity is connected to different cellular functions concerning the maintenance of chromatin structure and receptors and the degradation of abnormal proteins and cancerogenic progression. On this basis, this structural information opens the way to following studies focused on the definition of the biological potential of Gracilioether A and the rational development of novel USP5 inhibitors based on a new structural skeleton.

Findings from the Use of Spinal Anesthesia in the Laparoscopic Treatment of Extrauterine Pregnancy: Could It Represent an Alternative to General Anesthesia?

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 < 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.

Outpatient Use of Monoclonal Antibodies Casirivimab and Imdevimab in Pregnancy for Mild-to-Moderate Coronavirus Disease 2019.

OBJECTIVE: The aim of this study was to report the use casirivimab/imdevimab therapy in pregnant women with moderate coronavirus disease 2019 (COVID-19). STUDY DESIGN: We report 12 cases of unvaccinated pregnant patients with mild-to-moderate COVID-19 treated with casirivimab/imdevimab. RESULTS: Twelve unvaccinated pregnant patients with mild-to-moderate COVID-19 received casirivimab/imdevimab at the dose of 1200/1200 mg by intravenous infusion over 60 minutes. All women were managed outpatient. None experienced severe adverse drug reaction and none progressed to severe disease. CONCLUSION: Casirivimab/imdevimab should be considered for outpatient treatment of unvaccinated pregnant women with mild-to-moderate COVID-19 to decrease the risk of severe disease. KEY POINTS: · Casirivimab/imdevimab is not well studied in pregnant women.. · Casirivimab/imdevimab in pregnant women with mild-to-moderate COVID-19 decreases the risk of severe disease.. · Casirivimab/imdevimab in pregnant women with mild-to-moderate COVID-19 is well tolerated..

Ultra-low-impact laparoscopy: a new concept for a minimally invasive surgery.

INTRODUCTION: Minimally invasive surgery is considered the gold standard for the treatment of gynecological diseases. Our study aims to assess the effectiveness of the new concept of ultra-low-impact laparoscopy as a combination of low-impact laparoscopy, consisting in the use of miniaturized instruments through 3-5mm ports and low-pressure pneumoperitoneum, with regional anesthesia to evaluate the perioperative outcomes. METHODS: A cross-sectional study was performed from May 2023 to December 2023, to enroll 26 women affected by benign gynecological disease and threated by mini-invasive surgical approach. The surgical procedures were performed following the low-impact laparoscopy protocol and the regional anesthesia protocol. The postoperative pain, nausea, and vomiting and the antiemetic/analgesic intake were evaluated. Postoperative surgical and anesthesiological variables were analyzed. RESULTS: Operative time was within 90 min (41.1 ± 17.1 mean ± standard deviation (SD)) and no conversion to laparotomy or general anesthesia was required. According to VAS score, the postoperative pain during the whole observation time was less than 3 (mean). Faster resumption of bowel motility (6.5 ± 2.1 mean ± SD) and women's mobilization (3.1 ± 0.7 mean ± SD) were observed as well as low incidence of post-operative nausea and vomit. Early discharge and patient's approval were recorded. Intraoperatively pain score was assessed on Likert scale during all stages. CONCLUSION: Ultra-low-impact laparoscopy showed to provide a satisfying recovery experience for patients in terms of short hospital stays, cosmetic result, and pain relief, without compromising surgical outcomes. The encouraging results lead us to recruit a greater number of patients to validate our technique as a future well-established produce.

C-section technique vs minilaparotomy after minimally invasive uterine surgery: a retrospective cohort study.

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.

Identification of honokiol-based scaffold to design tankyrase 1/2 inhibitors by in silico and in vitro studies.

Recently, we identified magnolol bioinspired derivatives as new Tankyrase 1/2 (TNKS1/2) inhibitors by our Inverse Virtual Screening protocol. Based on these findings, in the present contribution, we enlarged our investigation of neolignans to the natural product honokiol (1) and a group of its analogues (2-8). By integrating in silico analysis and Surface Plasmon Resonance experiments, we demonstrated the binding of 1 (honokiol), 2, 6 and 7 towards TNKS2. Furthermore, we also proved the binding specificity of 1 and 7 against TNKS2, while 2 and 6 were found to be also TNSK1 binders, along with 4. Promising antiproliferative activity in A549 cancer cell line were observed for 1 and 6, with honokiol (1) presenting a higher potency than the well-known TNKS2 inhibitor XAV939. Collectively, these outcomes suggest that the honokiol-based scaffold can be employed to design novel anti-cancer therapeutic agents.

Fatty Acid Synthase as Interacting Anticancer Target of the Terpenoid Myrianthic Acid Disclosed by MS-Based Proteomics Approaches.

This research focuses on the target deconvolution of the natural compound myrianthic acid, a triterpenoid characterized by an ursane skeleton isolated from the roots of Myrianthus arboreus and from Oenothera maritima Nutt. (Onagraceae), using MS-based chemical proteomic techniques. Application of drug affinity responsive target stability (DARTS) and targeted-limited proteolysis coupled to mass spectrometry (t-LiP-MS) led to the identification of the enzyme fatty acid synthase (FAS) as an interesting macromolecular counterpart of myrianthic acid. This result, confirmed by comparison with the natural ursolic acid, was thoroughly investigated and validated in silico by molecular docking, which gave a precise picture of the interactions in the MA/FAS complex. Moreover, biological assays showcased the inhibitory activity of myrianthic acid against the FAS enzyme, most likely related to its antiproliferative activity towards tumor cells. Given the significance of FAS in specific pathologies, especially cancer, the myrianthic acid structural moieties could serve as a promising reference point to start the potential development of innovative approaches in therapy.

Identification of Novel Bromodomain-Containing Protein 4 (BRD4) Binders through 3D Pharmacophore-Based Repositioning Screening Campaign.

A 3D structure-based pharmacophore model built for bromodomain-containing protein 4 (BRD4) is reported here, specifically developed for investigating and identifying the key structural features of the (+)-JQ1 known inhibitor within the BRD4 binding site. Using this pharmacophore model, 273 synthesized and purchased compounds previously considered for other targets but yielding poor results were screened in a drug repositioning campaign. Subsequently, only six compounds showed potential as BRD4 binders and were subjected to further biophysical and biochemical assays. Compounds 2, 5, and 6 showed high affinity for BRD4, with IC50 values of 0.60 ± 0.25 µM, 3.46 ± 1.22 µM, and 4.66 ± 0.52 µM, respectively. Additionally, these compounds were tested against two other bromodomains, BRD3 and BRD9, and two of them showed high selectivity for BRD4. The reported 3D structure-based pharmacophore model proves to be a straightforward and useful tool for selecting novel BRD4 ligands.

Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCTs): A Scoping Review of 511 Cases, Including 2 New Cases.

Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCTs) are rare uterine mesenchymal neoplasms with uncertain biological potential. These tumors, which affect both premenopausal and postmenopausal women, usually have a benign clinical course. Nevertheless, local recurrences and distant metastases have been described. By analyzing 511 cases retrieved from individual reports and cases series, we provide here the most comprehensive overview of UTROSCT cases available in the literature, supplemented by two new cases of UTROSCTs. Case 1 was an asymptomatic 31-year-old woman who underwent a laparoscopic resection of a presumed leiomyoma. Case 2 was a 58-year-old postmenopausal woman with abnormal vaginal bleeding who underwent an outpatient hysteroscopic biopsy of a suspicious endometrial area. In both cases, immunohistochemical positivity for Calretinin and Inhibin was noted, typical for a sex cord differentiation. In both cases, total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed. In light of the available literature, no pathognomonic clinical or imaging finding can be attributed to UTROSCT. Patients usually present with abnormal uterine bleeding or pelvic discomfort, but 20% of them are asymptomatic. In most cases, a simple hysterectomy appears to be the appropriate treatment, but for women who wish to become pregnant, uterus-preserving approaches should be discussed after excluding risk factors. Age, tumor size, lymphovascular space invasion, nuclear atypia, and cervical involvement are not reliable prognostic factors in UTROSCT. The current research suggests that aggressive cases (with extrauterine spread or recurrence) can be identified based on a distinct genetic and immunohistochemical phenotype. For instance, UTROSCTs characterized by GREB1::NCOA1-3 fusions and PD-L1 molecule expression appear to be predisposed to more aggressive behaviors and recurrence, with GREB1::NCOA2 being the most common gene fusion in recurrent tumors. Hence, redefining the criteria for UTROSCTs may allow a better selection of women suitable for fertility-sparing treatments or requiring more aggressive treatments in the future.

Hysteroscopy and weight loss in treatment of endometrial cancer: case report and literature review.

Fertility-sparing treatments have become important for young women with atypical endometrial hyperplasia (AEH) or endometrial carcinoma (EC) who wish to preserve their reproductive potential. Evidence indicates a strong relationship between weight and EC and the effect of weight loss on reducing the risk of EC. We report the case of a young obese woman with a body mass index (BMI) of 46.6 kg/m2, diagnosed with grade 2 endometrial endometrioid adenocarcinoma, who underwent a combined fertility-sparing treatment with hysteroscopic resection followed by insertion of a levonorgestrel intrauterine system. After twelve months of failure to achieve a complete response, bariatric surgery was proposed to lose weight and improve the response to treatment. Histologic regression was achieved three months after surgery, with a weight loss of 30 kg and fifteen months after combined treatment of endometrial cancer. We reviewed the literature to summarize the evidence on the role of bariatric surgery and weight loss in modifying the oncologic and reproductive outcomes of women undergoing fertility-sparing treatment for atypical endometrial lesions.

Hysteroscopic resection vs ultrasound-guided dilation and evacuation for treatment of cesarean scar ectopic pregnancy: a randomized clinical trial.

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/m2 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.

Target identification by structure-based computational approaches: Recent advances and perspectives.

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.

2-Substituted 1,5-benzothiazepine-based HDAC inhibitors exert anticancer activities on human solid and acute myeloid leukemia cell lines.

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 × 103 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 IC50 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 ≤ IC50 ≤ 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.

A Classic Photochemical Approach Inducing an Unexpected Rearrangement: Exploring the Photoreactivity of Pentacyclic Triterpenic Acids.

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 Δ1-3-oxo-pentacyclic triterpenic acids gaining access to a new class of natural-unnatural 5(10→1)abeo-pentacyclic triterpenic acids.

Exploring the chemical space of functionalized [1,2,4]triazolo[4,3-a]quinoxaline-based compounds targeting the bromodomain of BRD9.

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 IC50 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.

How endocervicoscopy can impact obstetric outcomes in women undergoing LEEP for CIN2 + : a retrospective cohort analysis.

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).