Nickel-Catalyzed Reductive Protocol to Access Silacyclobutanes with Unprecedented Functional Group Tolerance.

While significant progress has been made in the area of transition metal-catalyzed ring-opening and formal cycloaddition reactions of 1,1-disubstituted silacyclobutanes (SCBs), synthesizing these SCBs-particularly those bearing additional functional groups-continues to present synthetic challenges. In this context, we present a novel Ni-catalyzed reductive coupling reaction that combines 1-chloro-substituted silacyclobutanes with aryl or vinyl halides and pseudohalides, thereby obviating the need for organometallic reagents. This method facilitates the generation of 1,1-disubstituted silacyclobutanes with a remarkable tolerance for various functional groups. This approach serves as a complementary and more step-economical alternative to the commonly used yet moisture- and air-sensitive nucleophilic substitution reactions involving Grignard or lithium reagents. Our initial mechanistic studies indicate that this reaction is initiated by oxidative cleavage of the Si-Cl bond in 1-chlorosilacyclobutanes, which represents a distinct mechanism from the previously documented reductive coupling processes involving carbon electrophiles and chlorosilanes.

Case report: A case report of co-morbidity of cervical intraepithelial neoplasia III and urethral cancer associated with HPV16.

In this report, we present a case of a woman with concurrent cervical intraepithelial neoplasia grade III (CIN III) and urethral cancer, both associated with HPV16 infection. This unique case was initially brought to attention due to postmenopausal vaginal bleeding, despite the absence of urological symptoms and negative tumor markers. An unexpected discovery of pelvic lymph node metastasis during a hysterectomy intended for CIN III highlighted the rare coexistence of these conditions, with urethral cancer also linked to HPV-16 within the urethral lesion. This case emphasizes the diagnostic challenges faced by HPV-related cervical lesions and the critical need for increased vigilance, even when urological symptoms are not apparent. The findings underline the potential complexity of HPV-associated lesions and advocate for comprehensive screening strategies to ensure the timely detection and management of such intricate cases.

19F-NMR studies of the impact of different detergents and nanodiscs on the A2A adenosine receptor.

For the A2A adenosine receptor (A2AAR), a class A G-protein-coupled receptor (GPCR), reconstituted in n-dodecyl-ß-D-maltoside (DDM)/|||||cholesteryl hemisuccinate (CHS) mixed micelles, previous 19F-NMR studies revealed the presence of multiple simultaneously populated conformational states. Here, we study the influence of a different detergent, lauryl maltose neopentyl glycol (LMNG) in mixed micelles with CHS, and of lipid bilayer nanodiscs on these conformational equilibria. The populations of locally different substates are pronouncedly different in DDM/|||||CHS and LMNG/|||||CHS micelles, whereas the A2AAR conformational manifold in LMNG/|||||CHS micelles is closely similar to that in the lipid bilayer nanodiscs. Considering that nanodiscs represent a closer match of the natural lipid bilayer membrane, these observations support that LMNG/|||||CHS micelles are a good choice for reconstitution trials of class A GPCRs for NMR studies in solution.

Two-Dimensional NMR Spectroscopy of the G Protein-Coupled Receptor A2AAR in Lipid Nanodiscs.

Eight hundred and twenty-six human G protein-coupled receptors (GPCRs) mediate the actions of two-thirds of the human hormones and neurotransmitters and over one-third of clinically used drugs. Studying the structure and dynamics of human GPCRs in lipid bilayer environments resembling the native cell membrane milieu is of great interest as a basis for understanding structure-function relationships and thus benefits continued drug development. Here, we incorporate the human A2A adenosine receptor (A2AAR) into lipid nanodiscs, which represent a detergent-free environment for structural studies using nuclear magnetic resonance (NMR) in solution. The [15N,1H]-TROSY correlation spectra confirmed that the complex of [u-15N, ~70% 2H]-A2AAR with an inverse agonist adopts its global fold in lipid nanodiscs in solution at physiological temperature. The global assessment led to two observations of practical interest. First, A2AAR in nanodiscs can be stored for at least one month at 4 °C in an aqueous solvent. Second, LMNG/CHS micelles are a very close mimic of the environment of A2AAR in nanodiscs. The NMR signal of five individually assigned tryptophan indole 15N-1H moieties located in different regions of the receptor structure further enabled a detailed assessment of the impact of nanodiscs and LMNG/CHS micelles on the local structure and dynamics of A2AAR. As expected, the largest effects were observed near the lipid-water interface along the intra- and extracellular surfaces, indicating possible roles of tryptophan side chains in stabilizing GPCRs in lipid bilayer membranes.

The Application of Radiolabeled Targeted Molecular Probes for the Diagnosis and Treatment of Prostate Cancer.

Radiopharmaceuticals targeting prostate-specific membrane antigens (PSMA) are essential for the diagnosis, evaluation, and treatment of prostate cancer (PCa), particularly metastatic castration-resistant PCa, for which conventional treatment is ineffective. These molecular probes include [68Ga]PSMA, [18F]PSMA, [Al18F]PSMA, [99mTc]PSMA, and [89Zr]PSMA, which are widely used for diagnosis, and [177Lu]PSMA and [225Ac]PSMA, which are used for treatment. There are also new types of radiopharmaceuticals. Due to the differentiation and heterogeneity of tumor cells, a subtype of PCa with an extremely poor prognosis, referred to as neuroendocrine prostate cancer (NEPC), has emerged, and its diagnosis and treatment present great challenges. To improve the detection rate of NEPC and prolong patient survival, many researchers have investigated the use of relevant radiopharmaceuticals as targeted molecular probes for the detection and treatment of NEPC lesions, including DOTA-TOC and DOTA-TATE for somatostatin receptors, 4A06 for CUB domain-containing protein 1, and FDG. This review focused on the specific molecular targets and various radionuclides that have been developed for PCa in recent years, including those mentioned above and several others, and aimed to provide valuable up-to-date information and research ideas for future studies.

Squamous cell carcinoma in mature cystic teratoma of the ovary induced by human papillomavirus 16 infection: A case report and literature review.

RATIONALE: Mature cystic teratoma is the most common ovarian germ cell tumor. The malignant transformation of ovarian mature cystic teratoma (MCT) is very rare, but the prognosis is poor. We present a case of ovarian mature cystic teratoma with human papillomavirus infection and malignant transformation into ovarian squamous cell carcinoma (SCC). The occurrence of this case may prove that high-risk human papillomavirus infection is a pathogenic factor inducing malignant transformation of mature cystic teratoma to SCC. PATIENT CONCERNS: A 38-year-old woman with a solid cystic mass of 8 cm on the right ovary, and human papillomavirus (HPV) test of her cervix showed HPV-16 infection. DIAGNOSIS: The transvaginal ultrasound was performed, and there was a cystic solid mass of 5.9 × 4.5 × 5.5 cm in the right adnexal area with unclear cystic fluid and rich blood flow signals in the capsule wall. HPV test of cervix showed HPV-16 infection. Diagnostic suspicion: cystic teratoma. INTERVENTION: The patient signed an laparoendoscopic surgery was performed to remove the right ovarian mass. Intraoperative pathology consultation revealed the malignant transformation of mature teratoma of the right ovary and the formation of squamous or adeno-SCC. We performed laparoscopic comprehensive surgical staging (hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, pelvic and para-aortic lymph node dissection) were made. OUTCOMES: The operation was successful and the postoperative recovery was smooth, was discharged 7 days after operation. Now the patient is recovering well and is continuing chemotherapy as planned. CONCLUSION: HR-HPV infection might be a causal factor for inducing malignant transformation of ovarian MCT to SCC, and the Jumping metastasis of lymph nodes may be the characteristic of SCC-MCT, but further verification is still needed.

GPCR large-amplitude dynamics by 19F-NMR of aprepitant bound to the neurokinin 1 receptor.

Comparisons of G protein-coupled receptor (GPCR) complexes with agonists and antagonists based on X-ray crystallography and cryo-electron microscopy structure determinations show differences in the width of the orthosteric ligand binding groove over the range from 0.3 to 2.9 Å. Here, we show that there are transient structure fluctuations with amplitudes up to at least 6 Å. The experiments were performed with the neurokinin 1 receptor (NK1R), a GPCR of class A that is involved in inflammation, pain, and cancer. We used 19F-NMR observation of aprepitant, which is an approved drug that targets NK1R for the treatment of chemotherapy-induced nausea and vomiting. Aprepitant includes a bis-trifluoromethyl-phenyl ring attached with a single bond to the core of the molecule; 19F-NMR revealed 180° flipping motions of this ring about this bond. In the picture emerging from the 19F-NMR data, the GPCR transmembrane helices undergo large-scale floating motions in the lipid bilayer. The functional implication is of extensive promiscuity of initial ligand binding, primarily determined by size and shape of the ligand, with subsequent selection by unique interactions between atom groups of the ligand and the GPCR within the binding groove. This second step ensures the wide range of different efficacies documented for GPCR-targeting drugs. The NK1R data also provide a rationale for the observation that diffracting GPCR crystals are obtained for complexes with only very few of the ligands from libraries of approved drugs and lead compounds that bind to the receptors.

A survey of surgical team members' awareness and perceptions toward the implementation of the surgical safety checklist in gynecological and obstetrical operations.

ABSTRACT: The World Health Organization Surgical Safety Checklist was developed to improve communication in perioperative care, reduce mortality and complications of patients, and ensure the consistent use of procedures for safe surgery. Despite the increased awareness of the checklist, the implementation compliance is reported as low and the degree of completeness varies. This study aimed to explore the possible supportive factors for the effective implementation and to identify potential awareness and barriers to its implementation in gynecological and obstetrical operation.A survey using a cross-sectional design that included surgeons, anesthetists, and operating room nurses was performed. We used an online link to distribute the survey to all eligible surgical team members in our hospital. The survey contained various aspects of perceptions on the Surgical Safety Checklist and an open-ended question that allowed respondents to offer their opinions on the topic.The overall self-reported awareness of the checklist within each professional group was high. The awareness of surgeons was lower than that of operating room nurses, particularly in the Time-out section. Most participants believed that operating room nurses ranked the highest compliance to the protocols, while surgeons stayed the lowest. Active leadership with experienced operating room nurses, good training for surgical team members, and simplification of the checklist would be the positive factors for the effective implementation.Although there is a high acceptance and adequate self-reported awareness of the Surgical Safety Checklist, it is not always possible to implement it successfully. Our findings suggest that with experienced and effective leadership, barriers to implementation can be overcome. With positive perception and commitment, the Surgical Safety Checklist is easy to implement and it can make a profound improvement on the safety of surgical care. Moreover, a strategy of repetitive training and assessment on the part of the involved health care professionals may be necessary to further improve patients' safety during surgery.

LncRNA NEAT1 promotes proliferation of ovarian cancer cells and angiogenesis of co-incubated human umbilical vein endothelial cells by regulating FGF9 through sponging miR-365: An experimental study.

OBJECTIVE: To uncover the function of lncRNA NEAT1 in ovarian cancer (OC) cells and its mechanism. METHODS: The expression patterns of lncRNA NEAT1 and FGF9 in human OC cells and human ovarian epithelial cells was determined. OC cells were transfected with sh-NEAT1, pcDNA3.1-NEAT1, miR-365 mimic, miR-365 inhibitor or pcDNA3.1-NEAT1 + sh-NEAT1 before cell proliferation rate and cell clone formation rate were measured. After the transfected OC cells were co-cultivated with human umbilical vein endothelial cells (HUVECs), Matrigel angiogenesis assay tested angiogenesis of HUVECs; qRT-PCR and Western blot tested the expressions of vascular endothelial growth factor (VEGF), angiogenin 1 (Ang-1) and matrix metalloproteinase 2 (MMP2). Dual-luciferase reporter assay determined the targeted binding of NEAT1 and FGF9 to miR-365. RESULTS: LncRNA NEAT1 and FGF9 are over-expressed in OC cells. Knockdown of NEAT1 or FGF9, or over-expression of miR-365 results in decreased proliferation rate and cell clones as well as inhibited angiogenesis and down-regulated expressions of VEGF, Ang-1 and MMP2. Over-expression of NEAT1 or knockdown of miR-365 can reverse the effect caused by FGF9 knockdown. NEAT1 can down-regulate the expression of miR-365 while up-regulating that of FGF9. Dual-luciferase reporter assay determined that NEAT1 competes with FGF9 for binding to miR-365. CONCLUSION: LncRNA NEAT1 up-regulates FGF9 by sponging miR-365, thus promoting OC cell proliferation and angiogenesis of HUVECs.

Endometrial cancer combined with polycystic ovary syndrome in 9 women under 40-years old: A case report.

The aim of the present study was to discuss the clinicopathological characteristics of endometrial carcinoma in young females with polycystic ovary syndrome (PCOS), and to review the current literature. A total of 9 patients with histopathologically confirmed endometrial cancer in young females with PCOS at the West China Second Hospital of Sichuan University between December 2007 and September 2013 were included. The clinicopathological characteristics of the patients were analyzed. The age range of the patients was 24-38 years (median age, 29), all of the cases had abnormal vaginal bleeding and endometrioid adenocarcinoma was the most common histopathological subtype observed (8 cases, 88.9%). Of the patients, 2 had well-differentiated cases and 7 patients had moderately differentiated cases. None of the patients received regular PCOS treatments and did not turn up for regular check-ups before they were diagnosed with endometrial carcinoma. Additionally, 7 patients received staging laparotomy with a total abdominal hysterectomy and bilateral salpingo-oophorectomy, 1 patient underwent an endometrial resection under hysteroscopy and the final patient received a high-dose of medroxyprogesterone treatment without surgery. In conclusion, doctors should take into consideration that young women with PCOS may also exhibit an endometrial carcinoma, and diagnosing and treating the endometrial carcinoma as early as possible in the young patients with PCOS is necessary.

TGFBR2 Regulates Hedgehog Pathway and Cervical Cancer Cell Proliferation and Migration by Mediating SMAD4.

TGFBR2 serves as an initial regulator of the TGF-ß signaling pathway, and loss or reduction of its expression can lead to uncontrolled cell growth. This study was conducted to further explore the mechanism of TGFBR2/SMAD4 on the migration and proliferation of CC cells. Here, TGFBR2 and SMAD4 expressions in CC cells and control cells were measured. The expression patterns of TGFBR2 and SMAD4 in CC cells were verified in the TCGA database. After CC cells were transfected with pcDNA3.1-TGFBR2 or pcDNA3.1-SMAD4, or cotransfected with pcDNA3.1-TGFBR2 and si-SMAD4, Co-IP was utilized for identification of the interaction between TGFBR2 and SMAD4, CCK-8 assay for the assessment of CC cell proliferation, and flow cytometry for the performance of cell cycles. After that, the migration ability of CC cells was examined by cell scratch assay. The expression levels of Hedgehog signaling pathway-related proteins (GLI1 and PTCH) were assayed by Western blot. Lowly expressed TGFBR2 and SMAD4 in CC cells were displayed by the TCGA database. Overexpression of TGFBR2 restrained CC cell migration and proliferation abilities, while the coeffect of TGFBR2 overexpression and SMAD4 knockdown reversed these trends. Besides, highly expressed PTCH and lowly expressed GLI1 were found in CC cells with overexpression of TGFBR2 or SMAD4. The Hedgehog signaling inhibitor (GANT58) can substantially hinder the development of CC cells. Cells in pcDNA3.1-TGFBR2 + si-SMAD4 + GANT58 group had suppressed abilities of cell proliferation and migration than those in pcDNA3.1-TGFBR2 + si-SMAD4 group. Hedgehog pathway agonist (SAG) reversed the inhibitory effect of pcDNA3.1-TGFBR2 or pcDNA3.1-SMAD4 on CC cell biological function. Collectively, TGFBR2 restrains the migration and proliferation abilities of CC cells via mediating SMAD4 to partially block the Hedgehog signaling pathway.

LncRNA PVT1 epigenetically stabilizes and post-transcriptionally regulates FOXM1 by acting as a microRNA sponge and thus promotes malignant behaviors of ovarian cancer cells.

Accumulating evidence demonstrates that long noncoding RNAs (lncRNAs) may be involved in the regulation of cancer biology. PVT1, which is overexpressed in tumor samples, acts as an oncogenic promoter in several kinds of cancers, including ovarian cancer. However, the mechanisms of its regulation of malignant behaviors in ovarian cancer remain largely unknown. In this study, the expression of PVT1 in several ovarian cancer cell lines was analyzed by qRT-PCR. The effect of PVT1 on malignant behaviors, including cell proliferation, migration and invasion, was analyzed. The posttranscriptional regulation of FOXM1 by PVT1 was analyzed by western blotting. The results illustrated that PVT1 acted as a sponge and bound miR-370 on two binding sites. The expression of PVT1 positively regulated malignant behaviors in ovarian cancer cells, including cell proliferation, migration and invasion, which could be reversed by the introduction of miR-370 mimics. Sponged miR-370 failed to posttranscriptionally regulate FOXM1, which resulted in the promotion of malignant behavior. PVT1 was also found to bind to FOXM1 directly and stabilize the FOXM1 protein. The promoting effect of PVT1 on malignant behaviors and chemoresistance to cisplatin could be reversed by knockdown of FOXM1 and introduction of miR-370 mimics. Together, these results suggest that lncRNA PVT1 promotes malignant behavior and induces chemoresistance in ovarian cancer by epigenetic and posttranscriptional regulation of FOXM1.

The outcomes and quality of life of young patients undergoing adjuvant radiotherapy versus non-radiotherapy following surgery treating early FIGO stage cervical squamous cell cancer in southwestern China.

BACKGROUND: The incidence of cervical cancer in young women is rising, and squamous cell carcinoma makes up a great percentage of the histological types. The presence of aggressive pathologic risk factors following patients' primary surgery may warrant the use of adjuvant radiotherapy. It is important to weigh up the risks and benefits of using adjuvant radiotherapy for each young patient so as to maximize their prognosis while minimizing the treatment-related morbidity. METHODS: A retrospective study was performed. It consisted of 97 patients under 35 years old who were diagnosed with cervical squamous cell carcinoma and underwent treatment at West China Second University Hospital between December 2009 and January 2014. Five-year follow-up, prognostic risks, long-term radiation toxicity, female sexual function, and quality of life were investigated. RESULTS: Adjuvant radiotherapy did improve the prognosis of young patients with lymph node metastases. However, there were few significant differences in progress-free survival and overall survival for the young patients without lymph node metastases following adjuvant radiotherapy. Besides, young patients who took radiotherapy exhibited greater intestinal dysfunction, more severe lower extremities edema, greater sexual dysfunction, and worse long-term quality of life. CONCLUSION: Young patients with early-stage cervical squamous cell carcinoma without lymph node metastases who have undergone the primary surgery should be counseled in detail before the decision to use adjuvant radiotherapy can be made. The counseling should emphasize not only the benefit that local recurrence rates can be reduced, but also the risks that treatment-related side effects could increase and lower QoL could occur.

3-Hydroxyisoindolin-1-one derivates: Synthesis by palladium-catalyzed CH activation as BRD4 inhibitors against human acute myeloid leukemia (AML) cells.

Bromodomain protein 4 (BRD4) is a member of the bromodomain and extra-terminal domain (BET) protein family, which plays a key role in transcriptional regulation. Recent biological and pharmacological studies have enabled linking of the BET bromodomains with diseases, including inflammation and cancer, suggesting that bromodomains are druggable targets. In this study, we made further structural modifications of our previously reported BRD4 inhibitors, to develop new chemical scaffold 3-Hydroxyisoindolin-1-One. Then a series of compounds (10a-q) were synthesized via palladium-catalyzed CH activation and BRD4-inhibitory activities and anti-proliferative effects of these compounds were evaluated. Compound 10e exhibited excellent BRD4-inhibitory activity with IC50 value of 80 nM and anti-proliferation potency with IC50 value of 365 nM in HL-60 (humanpromyelocytic leukemia) cancer cell lines. We have demonstrated compound 10e modulated the intrinsic apoptotic pathway. In conclusion, these results suggested that compound 10e could be utilized as a BRD4 inhibitor for further leukemia treatment.

Internal iliac artery balloon occlusion as a hemostatic method for spontaneous rupture of vulvar hematoma during delivery: A case report.

Spontaneous rupture of a vulvar hematoma during delivery is a relatively uncommon event and may cause excessive hemorrhage. Exact identification of anatomic structures and bleeding points is challenging. We herein present a case involving a pregnant woman at 39 weeks' gestation with a large vulvar hematoma that spontaneously ruptured during the second stage of labor, likely due to rupture of varices in the vulva or vagina. It was difficult to accurately expose and suture the deep bleeding points. The estimated blood loss volume was 1591 mL, and the hemoglobin concentration dropped from 132 g/L before delivery to 84 g/L after delivery. To prevent hemorrhagic shock, bilateral internal iliac artery balloon occlusion was performed and proved to be an effective way to achieve hemostasis. Once hemostasis was established, ligation of the bleeding sites and suturing of all dead space were rapidly completed. Bilateral internal iliac artery balloon occlusion can be used as an effective treatment for excessive vaginal bleeding. The presence of varices or hemangiomas in the vulva or vagina should be carefully checked during antenatal care.

Long non-coding RNA HOTTIP is able to predict poor prognosis in various neoplasms: A meta-analysis.

HOXA distal transcript antisense RNA (HOTTIP), a critical oncogenic long non-coding RNA, has been reported to be aberrantly regulated in various cancer types. The present meta-analysis aimed to investigate HOTTIP as a potential clinical applicable prognostic biomarker in malignant neoplasms. Literature collections were performed by searching the electronic databases, PubMed and Web of Science (up to July 20, 2016). All the relevant searches were conducted to identify the association of HOTTIP with the overall survival (OS) rate. A total of six articles consisting of 508 patients were included in the present meta-analysis. The results suggested that the overexpression of HOTTIP is closely correlated with poor OS (hazard ratio=2.28; 95% confidence interval=1.71-3.04; P=0.000). In conclusion, the present meta-analysis has demonstrated that an increased expression level of HOTTIP is correlated with poor OS in different types of cancer, suggesting that HOTTIP potentially serves as a reliable prognostic biomarker in different types of cancer.

Design, synthesis and biological evaluation of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as BRD4 inhibitors.

BRD4 is an attractive target for antitumor due to its important role in regulation of gene transcription. In this paper, we synthesized a series of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as potent BRD4 inhibitors and evaluated their BRD4 inhibitory activities in vitro and anti-proliferation effects on tumor cells. Gratifyingly, compound 10j exhibited robust potency of BRD4(1) and BRD4(2) inhibition with IC50 values of 130 and 76nM respectively. Docking studies were performed to explain the structure-activity relationship. Furthermore, compound 10j potently inhibited cell proliferation in BRD4-sensitive cell lines HL-60 and MV4-11 with IC50 value of 0.57 and 0.18µM respectively. Activity on BRD4-independent K562 cell was weaker than on BRD4-sensitive lines. Overall, these results suggest that compound 10j is a potential BRD4 inhibitor deserving further investigation for cancer treatment.

Hollow-structured conjugated porous polymer derived Iron/Nitrogen-codoped hierarchical porous carbons as highly efficient electrocatalysts.

Iron and nitrogen (Fe/N) co-doped porous carbons have already shown great potential as electrocatalysts for oxygen reduction reaction in alkaline media. However, it still remains a great challenge to finely integrate a hierarchical porous structure and Fe/N co-doping effect into one material at the same time. In this work, a rational design toward Fe/N-codoped hierarchical porous carbon spheres was developed by the formation of an iron-porphyrin-containing conjugated microporous polymer sphere with hollow structure (HCMP) through a silica sphere template directed condensation of pyrrole and 1,4-phthalaldehyde, then etched with NaOH, and treated with FeCl2. The resulting HCMP-Fe polymer was readily converted to a series of Fe/N co-doped hierarchical porous carbons (HPC-Fe/N-X, X=700-900) upon pyrolysis at different temperatures and etching treatment. These porous carbons exhibit the high specific surface areas up to 518m2g-1 and the contents of N and Fe up to 3.28at.% and 0.85wt.%, respectively. Benefiting from the high surface area, Fe/N co-doping character, HPC-Fe/N-700 exhibited excellent electrochemical catalytic performance for oxygen reduction reaction under alkaline condition (0.1M KOH) with a low half-wave potential (0.84V), a dominant four-electron transfer mechanism (n=3.89 at 0.65V), as well as a high diffusion limiting current density (JL=5.19mAcm-2), comparable to those porous carbon-based ORR catalysts with excellent electrochemical performance.