BV-operators and the secondary Hochschild complex

We introduce the notion of a BV-operator $\Delta =\lbrace \Delta ^n:V^n\longrightarrow V^{n-1}\rbrace _{n\ge 0}$ on a homotopy $G$-algebra $V^\bullet$ such that the Gerstenhaber bracket on $H(V^\bullet )$ is determined by $\Delta$ in a manner similar to the BV-formalism. As an application, we produce a BV-operator on the cochain complex defining the secondary Hochschild cohomology of a symmetric algebra $A$ over a commutative algebra $B$. In this case, we also show that the operator $\Delta ^\bullet$ corresponds to Connes’ operator

BV-operators and the secondary Hochschild complex

We introduce the notion of a BV-operator $\Delta =\lbrace \Delta ^n:V^n\longrightarrow V^{n-1}\rbrace _{n\ge 0}$ on a homotopy $G$-algebra $V^\bullet$ such that the Gerstenhaber bracket on $H(V^\bullet )$ is determined by $\Delta$ in a manner similar to the BV-formalism. As an application, we produce a BV-operator on the cochain complex defining the secondary Hochschild cohomology of a symmetric algebra $A$ over a commutative algebra $B$. In this case, we also show that the operator $\Delta ^\bullet$ corresponds to Connes’ operator

MBRRACE in simulation: an evaluation of a multi-disciplinary simulation training for medical emergencies in obstetrics (MEmO)

he majority of maternal deaths in the UK are due to pre-existing or new-onset medical conditions, known as ‘indirect deaths’. The MBRRACE report identified serious gaps in clinicians’ human factors skills, including communication, leadership and teamwork, which contributed to maternal death. In response, we developed the first multi-disciplinary simulation-based training programme designed to address Medical Emergencies in Obstetrics (MEmO). Employing a mixed methods design, this study evaluated the educational impact of this training programme on the healthcare staff (n = 140), including the medical doctors (n = 91) and the midwives (n = 49). The training improved participants’ clinical management of medical deterioration in pregnancy (p=.003) alongside improving their human factors skills (p=.004). Furthermore, participants reported the translation of these skills to their routine clinical practice. This flexible training is responsive to the changing national needs and contextualises the MBRRACE findings for healthcare staff. It is a promising avenue for reducing the rates of in-direct death in pregnancy. Impact statement What is already known on this subject? The majority of maternal deaths in the UK are due to pre-existing or new-onset medical conditions. The management of medical conditions in pregnancy relies on a multi-professional approach. However, serious gaps in clinicians’ human factors skills, highlighted by the MBRRACE report, may contribute to maternal death. What do the results of this study add? This study evaluated the first multi-disciplinary, simulation-based training programme designed to address Medical Emergencies in Obstetrics (MEmO). Training significantly improved participants’ management of medical deterioration in pregnancy and human factors skills, particularly in the areas of leadership, communication and teamwork. Moreover, the participants learning translated into their clinical practice. What are the implications of these findings for clinical practice and/or further research? The delivery of multi-disciplinary team training for all healthcare staff involved in the complex management of medical conditions in pregnancy can help develop a greater understanding of others’ professional roles, and demonstrate the importance of interprofessional teamwork. Furthermore, it provides the space to reflect on team working approaches, including the leadership and professional autonomy, and their potential impact on patient care. Future research should evaluate the impact of this training on the objective outcome measures of medical emergencies in pregnancy

A novel curcumin-based vaginal cream Vacurin selectively eliminates apposed human cervical cancer cells

Objective. Human papillomavirus (HPV) infections remain a leading cause of mortality worldwide. In the U.S. strategies via screening and vaccination prevent HPV-associated cervical neoplasms, but consume im- mense healthcare costs. The spice component curcumin has potent anticancer and antiviral properties, which have been difficult to harness as a treatment, due to its poor systemic bioavailability. This project tests the possibility of developing a curcumin-based therapy for cervical cancer. Methods. Using four HPV(+) cervical cancer cell lines and normal fibroblasts we first tested the selectivity and potency of curcumin in eliminating HPV(+) cells. Subsequently, we developed a curcumin-based cervical cream and tested its efficacy in eliminating apposed HPV(+) cells and also its possible side effects on the vaginal epithelium of healthy mice. Results. Curcumin selectively eliminates a variety of HPV(+) cervical cancer cells (HeLa, ME-180, SiHa, and SW756), suppresses the transforming antigen E6, dramatically inhibits the expression of the pro-cancer protein epidermal growth factor receptor (EGFR), and concomitantly induces p53. Additionally, Vacurin, a uniform colloidal solution of curcumin in a clinically used amphipathic vaginal cream, eliminates apposed HeLa cells while suppressing the expression of EGFR. In mice, daily intravaginal application of Vacurin for three weeks produced no change in body weight and when the mice were sacrificed, the vaginal tract epithelium showed no Vacurin-evoked adverse effects. Conclusion. We have developed a curcumin-based vaginal cream, which effectively eradicates HPV(+) cancer cells and does not affect non-cancerous tissue. Our preclinical data support a novel approach for the treatment of cervical HPV infection

Engineered reversal of drug resistance in cancer cells - metastases suppressor factors as change agents

Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/sensitive cells. To test this model, we focused on a group of genes called Metastasis Suppressor Genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50–60 %, in both culture conditions and also in tumors generated in mice, in contrast to control un-induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles

Possible Molecular Mechanisms Underlying the Development of Atherosclerosis in Cancer Survivors

Cancer survivors undergone treatment face an increased risk of developing atherosclerotic cardiovascular disease (CVD), yet the underlying mechanisms remain elusive. Recent studies have revealed that chemotherapy can drive senescent cancer cells to acquire a proliferative phenotype known as senescence-associated stemness (SAS). These SAS cells exhibit enhanced growth and resistance to cancer treatment, thereby contributing to disease progression. Endothelial cell (EC) senescence has been implicated in atherosclerosis and cancer, including among cancer survivors. Treatment modalities for cancer can induce EC senescence, leading to the development of SAS phenotype and subsequent atherosclerosis in cancer survivors. Consequently, targeting senescent ECs displaying the SAS phenotype hold promise as a therapeutic approach for managing atherosclerotic CVD in this population. This review aims to provide a mechanistic understanding of SAS induction in ECs and its contribution to atherosclerosis among cancer survivors. We delve into the mechanisms underlying EC senescence in response to disturbed flow and ionizing radiation, which play pivotal role in atherosclerosis and cancer. Key pathways, including p90RSK/TERF2IP, TGFβR1/SMAD, and BH4 signaling are explored as potential targets for cancer treatment. By comprehending the similarities and distinctions between different types of senescence and the associated pathways, we can pave the way for targeted interventions aim at enhancing the cardiovascular health of this vulnerable population. The insights gained from this review may facilitate the development of novel therapeutic strategies for managing atherosclerotic CVD in cancer survivors

Diagnostic imaging of cervical intraepithelial neoplasia based on hematoxylin and eosin fluorescence

Background Pathological classification of cervical intraepithelial neoplasia (CIN) is problematic as it relies on subjective criteria. We developed an imaging method that uses spectroscopy to assess the fluorescent intensity of cervical biopsies derived directly from hematoxylin and eosin (H&E) stained tissues. Methods Archived H&E slides were identified containing normal cervical tissue, CIN I, and CIN III cases, from a Community Hospital and an Academic Medical Center. Cases were obtained by consensus review of at least 2 senior pathologists. Images from H&E slides were captured first with bright field illumination and then with fluorescent illumination. We used a Zeiss Axio Observer Z1 microscope and an AxioVision 4.6.3-AP1 camera at excitation wavelength of 450–490 nm with emission captured at 515–565 nm. The 32-bit grayscale fluorescence images were used for image analysis. Results We reviewed 108 slides: 46 normal, 33 CIN I and 29 CIN III. Fluorescent intensity increased progressively in normal epithelial tissue as cells matured and advanced from the basal to superficial regions of the epithelium. In CIN I cases this change was less prominent as compared to normal. In high grade CIN lesions, there was a slight or no increase in fluorescent intensity. All groups examined were statistically different. Conclusion Presently, there are no markers to help in classification of CIN I-III lesions. Our imaging method may complement standard H&E pathological review and provide objective criteria to support the CIN diagnosis

Unique synergistic formulation of curcumin, epicatechin gallate and resveratrol, tricurin, suppresses HPV E6, eliminates HPV+ cancer cells, and inhibits tumor progression

Curcumin (from curry) (C) is highly potent against cervical cancer cells (CCC), but poor bioavailability has limited its clinical use. Similar natural polyphenols resveratrol (from grapes) (R), and epicatechin gallate (from green tea) (E) also display activity against CCC. By treating CCC (HeLa) with C, E, or R, or combinations of these compounds, we computed combination indices and observed a strong synergism among C, E, and R at the unique molar ratio 4:1:12.5. This combination, named as TriCurin, rapidly down regulated HPV18 E6 and NF-kB expression while concomitantly inducing the tumor suppressor protein p53 in HeLa cells. In the mouse c-Ha-ras and HPV16 E6, E7-expressing TC-1 CCC, both C and TriCurin elicited suppression of E6, induction of both p53 and acetyl-p53 (activated p53), and activation of caspase-3, but the TriCurinevoked changes were several-fold greater than that produced by curcumin (4.7-fold for E6 inhibition, and 2-fold, 6-fold, and 1.7-fold for the induction of p53, acetyl-p53, and active caspase-3, respectively). Consequently, TriCurin was more potent in killing TC-1 and HeLa cells. Intralesional TriCurin treatment of tumors generated in mice by subcutaneously implanting the TC-1 CCC caused an 80–90% decrease in tumor growth. The ability of C to eliminate HeLa cells was significantly stabilized when delivered as TriCurin than when delivered alone. Topical application of TriCurin dispersed in a cream base afforded efficient transfer of C across the skin. Subcutaneous TriCurin injection yielded no adverse effect in tumor-naïve healthy mice. Thus, TriCurin is a safe and promising therapeutic agent against HPV-associated disease