Discovery of AL-GDa62 as a Potential Synthetic Lethal Lead for the Treatment of Gastric Cancer.

Diffuse gastric cancer and lobular breast cancer are aggressive malignancies that are frequently associated with inactivating mutations in the tumor suppressor gene CDH1. Synthetic lethal (SL) vulnerabilities arising from CDH1 dysfunction represent attractive targets for drug development. Recently, SLEC-11 (1) emerged as a SL lead in E-cadherin-deficient cells. Here, we describe our efforts to optimize 1. Overall, 63 analogues were synthesized and tested for their SL activity toward isogenic mammary epithelial CDH1-deficient cells (MCF10A-CDH1-/-). Among the 26 compounds with greater cytotoxicity, AL-GDa62 (3) was four-times more potent and more selective than 1 with an EC50 ratio of 1.6. Furthermore, 3 preferentially induced apoptosis in CDH1-/- cells, and Cdh1-/- mammary and gastric organoids were significantly more sensitive to 3 at low micromolar concentrations. Thermal proteome profiling of treated MCF10A-CDH1-/- cell protein lysates revealed that 3 specifically inhibits TCOF1, ARPC5, and UBC9. In vitro, 3 inhibited SUMOylation at low micromolar concentrations.

Dental Visits for Autistic Children: A Qualitative Focus Group Study of Parental Perceptions.

INTRODUCTION: Patient groups who pose behavioral challenges during dental attendance may be offered more restricted dental treatment options. Unsuccessful participation with dental visit tasks and demands has been commonly reported for autistic children. OBJECTIVES: This study aimed to examine parental perceptions of difficulties associated with dental attendance and oral care for autistic children and young adults, to highlight reported challenges and potential adaptations, and to identify interventions that will encourage positive experiences of dental attendance. METHODS: Qualitative data were gathered through 2 focus groups with parents of primary school and secondary school pupils with autism, interviewed in separate groups. Questions about parents' perceptions of dental attendance and oral care were asked. The groups were audio-recorded and transcribed verbatim. The transcripts were analyzed and initial codes generated. Development of subthemes and themes followed a process of thematic analysis. RESULTS: Parental perceptions, which confirmed data from other studies, included the need for understanding and training, awareness of sensory issues, recognition of the individuality of autistic traits, time and clarity for communication, and factors affecting the confidence of parents to advocate in the clinical environment. Focus group participants identified the critical value of empathizing with an autistic perspective and highlighted the importance of positive oral health messages. They also noted the lack of understanding regarding the complexity of altering self-imposed, ritualistic dietary regimes and attempting to enact good dental preventive habits for their children. CONCLUSIONS: Analysis of data from parent focus groups provided a greater understanding of the needs and responsivity required for successful dental visits for autistic children and young adults. A range of potential interventions was identified and incorporated within a model of needs. Interventions based on Partnership Working, System Change, and Training of Dental Staff could be effective in reducing challenges posed by dental attendance for many children with autism. KNOWLEDGE TRANSFER STATEMENT: Sensory sensitivities, communication difficulties, comorbid intellectual disability, and dental anxiety are barriers to successful participation during dental attendance for autistic children. This research proposes that interventions supporting Partnership Working, System Change, and Training of Dental Staff can reduce challenges posed by dental attendance. The model of interventions developed as part of this project can be used by oral care teams to help reduce barriers and improve the success of dental visits for autistic children.

Dental RECUR Randomized Trial to Prevent Caries Recurrence in Children.

The purpose of this study was to determine the efficacy of a dental nurse-delivered intervention-the Dental RECUR Brief Negotiated Interview for Oral Health (DR-BNI)-in reducing the recurrence of dental caries in children who have a primary tooth extracted. It was based on a 2-arm multicenter randomized controlled trial with blinded outcome assessment. Participants were 5- to 7-y-old children (n = 241) scheduled to have primary teeth extracted in 12 UK centers. Test intervention parents (n = 119) received DR-BNI led by trained dental nurses. DR-BNI is a 30-min structured conversation informed by motivational interviewing with a forward focus to prevent future caries. Preventive goals are agreed, and a review appointment is made with child's general dental practitioner, who is advised to treat the child as being at high caries risk. The control intervention (n = 122) was a parent-nurse conversation about child's future tooth eruption, with advice given to visit a general dental practitioner as usual. At baseline, the DR-BNI group's mean dmft was 6.8, and the control group's was 6.3. A median of 5 teeth were extracted, mainly under general anesthesia. Final dental assessments were conducted by a single examiner visiting 189 schools 2 y after intervention; 193 (80%) of 241 children were examined. In the control group, 62% developed new caries in teeth that were caries-free or unerupted at baseline, as compared with 44% in the test group, a significant reduction (P = 0.021). The odds of new caries experience occurring were reduced by 51% in the DR-BNI group as compared with control. There was a 29% decrease in the relative risk of new caries experience in the DR-BNI group as compared with control. This single low-cost, low-intensity intervention was successful in significantly reducing the risk of recurrence of dental caries in children. This trial has implications for changing pediatric dental practice internationally. Training in and implementation of a motivational interviewing-informed brief intervention provides opportunities for dental nurses to facilitate behavior change improving the oral health of children at high caries risk (ISRCTN 24958829).

Surgical simulation supplements reproductive endocrinology and infertility fellowship training.

OBJECTIVE: To assess if a surgical boot camp improves laparoscopic skill among reproduction endocrinology and infertility (REI) fellows and increases fellow desire to incorporate surgical skills into practice and to examine whether fellowship in vitro fertilization (IVF) volume correlates with surgical efficiency. DESIGN: Prospective evaluation. SETTING: Simulation Center. PATIENTS: Forty REI fellows. INTERVENTIONS: Fellows were timed before and after training in laparoscopic suturing and knot tying and while using virtual simulators. Fellows were surveyed before boot camp on prior experience with IVF and reproductive surgery, and immediately and 1 month after boot camp on their desire to incorporate surgical skills into practice. MAIN OUTCOME MEASURES: Efficiency of laparoscopic suturing and knot tying before and after boot camp; likelihood and persistence of incorporating surgical skills into practice immediately and 1 month after boot camp; and correlation between fellowship IVF volume and fellow surgical efficiency. RESULTS: Fellows experienced significant improvement in laparoscopic suturing (44 sec), intracorporeal knot tying (82 sec), and extracorporeal knot tying (71 sec). Fellows reported being more likely to incorporate operative hysteroscopy (89%), operative laparoscopy (87%), and laparoscopic suturing (84%) into practice immediately following boot camp with no difference 1 month later. Fifty-four percent of fellows reported being more likely to perform robotic surgery after the boot camp, increasing to 70% 1 month later. There were weak correlations between IVF case volume and efficiency in laparoscopic suturing or hysteroscopic polypectomy (Spearman correlation coefficients, -0.14 and -0.03). CONCLUSIONS: An intensive surgical boot camp enhances surgical skill among REI fellows.

Management of paediatric humeral shaft fractures and associated nerve palsy.

PURPOSE: The aim of this study is to review the management of all paediatric humerus diaphyseal fractures treated at a single institution over a 20-year period. METHODS: Retrospective review from between 1996 and 2016 identified 96 humerus shaft fractures in paediatric patients (0 to 17 years). After excluding those deceased from inciting trauma, pathological and perinatal fractures, 80 patients remained for analysis. Data collected included age, fracture type, displacement, nerve palsy, treatment, complications and time to union. Radiographs were reviewed at the time of injury and at latest follow-up. RESULTS: Of 80 paediatric humeral diaphyseal fractures, 65 (81%) were treated with immobilization. In all, 15 (19%) fractures were treated with surgical stabilization. Most common indications were fracture displacement, open fractures and to improve mobilization in patients with multiple injuries. Fractures were stabilized with a plate (eight), flexible nails (five), external fixation (one) and percutaneous pinning (one). The operative group, compared with the nonoperative group, was older, had more high-energy mechanisms, more open fractures and increased fracture displacement. All patients in the nonoperative and operative groups went on to union with minimal complications. A nerve palsy was present in five patients (6%)with three of the five involving the radial nerve (4%). All nerve palsies were observed and had full neurological recovery. CONCLUSION: Over a 20-year period nonoperative management of paediatric humerus shaft fractures was successful in the majority of patients. Operative stabilization, when rarely indicated, had a low complication rate and improved radiographic alignment. All nerve injuries fully recovered without surgical intervention. LEVEL OF EVIDENCE: IV.

Are there missed opportunities for vaccinating against hepatitis B among people who inject drugs in the UK?

Sustaining the impact of hepatitis B virus (HBV) vaccination on incidence and prevalence of HBV infection requires increasing and maintaining the uptake of vaccine among those at risk. In recent years, the level of vaccine uptake among people who inject drugs (PWID) in the UK has levelled-off. Data (2015-2016) from the national unlinked-anonymous monitoring survey of PWID, an annual survey that collects data from PWID across England, Wales and Northern Ireland, were used to examine HBV vaccine uptake. Data from participants who had injected drugs during the previous year were used to investigate sources of hepatitis B vaccine doses as well as factors associated with vaccine uptake. Among the 3175 anti-HBc-negative participants, 3138 (99%) reported their vaccination status; 23% (714) reported no vaccine uptake. Among those not vaccinated, 447 (63%) reported being sexually active and 116 (16%) reported sharing needles and syringes. Majority of those not vaccinated reported accessing services in the previous year that could have provided hepatitis B vaccine doses. These missed opportunities for vaccinating of PWID indicate a need for additional targeted interventions.

Hysteroscopy and why macroscopic uterine factors matter for fertility.

For humans, the uterus is their first home. Accurate evaluation and effective therapy are central to optimizing the conditions for implantation and sustained pregnancy. For macroscopic intracavitary disease, hysteroscopy remains the gold standard for diagnosis and treatment. We review the role of hysteroscopy before fertility therapies. We also address intracavitary pathologies and their relevance to procreative outcomes. Controversies in the literature are noted and clarified, and trends in the field of hysteroscopy are identified regarding how they will influence the future of reproductive care and women's health.

Societal pressures and procreative preferences for gay fathers successfully pursuing parenthood through IVF and gestational carriers.

This retrospective study surveyed decision-making and challenges among 78 gay cisgender male couples utilizing in-vitro fertilization (IVF) and a gestational carrier. While most couples (67.1%) found the decision to actively pursue fertility treatment 'not difficult', 32.9% felt that it was 'somewhat difficult' or 'very or extremely difficult'. Almost 30% of couples had not undertaken financial planning for treatment, which introduced delays of > 2 years for 25.3% of participants. Conceiving twins was 'important to very important' in 52.3% of couples, and 84.2% of couples chose to transfer two embryos to 'increase the odds' or reach an ideal family size in a single attempt despite increased complications with multiple pregnancies. Paternal leave was granted for one partner in 47.3% of couples, and for both partners in 43.2% of couples. One-third of couples reported experiencing discrimination, prompting a partner to seek employment, and 38% changed jobs or careers. For 80.3% of couples, the estimated cost exceeded US$100,000. Couples where one partner was aged > 50 years were significantly more likely to find the decision to actively pursue fertility treatment 'very or extremely difficult' (28.6%), and less likely to agree on becoming parents (64.3%). Gay male couples undergoing assisted reproduction face challenges regarding decision-making, lack of infertility benefits and discrimination, which appear to be influenced by age and country of residence. Policy and educational changes are needed, including broader fertility benefits, more egalitarian parental leave, and greater awareness of risks inherent to multiple gestation.

E-cadherin-deficient cells have synthetic lethal vulnerabilities in plasma membrane organisation, dynamics and function.

BACKGROUND: The E-cadherin gene (CDH1) is frequently mutated in diffuse gastric cancer and lobular breast cancer, and germline mutations predispose to the cancer syndrome Hereditary Diffuse Gastric Cancer. We are taking a synthetic lethal approach to identify druggable vulnerabilities in CDH1-mutant cancers. METHODS: Density distributions of cell viability data from a genome-wide RNAi screen of isogenic MCF10A and MCF10A-CDH1-/- cells were used to identify protein classes affected by CDH1 mutation. The synthetic lethal relationship between selected protein classes and E-cadherin was characterised by drug sensitivity assays in both the isogenic breast MCF10A cells and CDH1-isogenic gastric NCI-N87. Endocytosis efficiency was quantified using cholera toxin B uptake. Pathway metagene expression of 415 TCGA gastric tumours was statistically correlated with CDH1 expression. RESULTS: MCF10A-CDH1-/- cells showed significantly altered sensitivity to RNAi inhibition of groups of genes including the PI3K/AKT pathway, GPCRs, ion channels, proteosomal subunit proteins and ubiquitinylation enzymes. Both MCF10A-CDH1-/- and NCI-N87-CDH1-/- cells were more sensitive than wild-type cells to compounds that disrupted plasma membrane composition and trafficking, but showed contrasting sensitivities to inhibitors of actin polymerisation and the chloride channel inhibitor NS3728. The MCF10A-CDH1-/- cell lines showed reduced capacity to endocytose cholera toxin B. Pathway metagene analysis identified 20 Reactome pathways that were potentially synthetic lethal in tumours. Genes involved in GPCR signalling, vesicle transport and the metabolism of PI3K and membrane lipids were strongly represented amongst the candidate synthetic lethal genes. CONCLUSIONS: E-cadherin loss leads to disturbances in receptor signalling and plasma membrane trafficking and organisation, creating druggable vulnerabilities.

Using the EngagedMD multimedia platform to improve informed consent for ovulation induction, intrauterine insemination, and in vitro fertilization.

OBJECTIVE: To study patient and provider feedback on how a multimedia platform (EngagedMD) helps patients to understand the risks and consequences of in vitro fertilization (IVF), ovulation induction (OI), and intrauterine insemination (IUI) treatments and the impact of the informed consent process. DESIGN: Prospective survey study. SETTING: IVF units in the United States. PATIENT(S): Six-thousand three-hundred and thirty-three patients who viewed the multimedia platform before IVF or OI-IUI treatment at 13 U.S. IVF centers and 128 providers. INTERVENTION(S): Quantitative survey with 17 questions. MAIN OUTCOME MEASURE(S): Assessment of the impact of a multimedia platform on patient anxiety, comprehension, and satisfaction and provider/nurse feedback related to the informed consent process. RESULT(S): The survey was completed by 3,097 respondents (66% IVF treatment; 34% OI-IUI treatment) and 44 providers. Overall, 93% felt the media platform was intuitive, and 90% and 95% felt it had appropriate duration and detail, respectively. Most agreed/strongly agreed it better prepared them to consent (88%), increased their comfort in pursuing treatment (77%) and increased their satisfaction with their care (83%). Compared with the OI-IUI group, statistically significantly more participants who viewed the IVF media platform strongly agreed that the comprehension questions reinforced key concepts (47% vs. 40%), educated them about treatment risks (55% vs. 44%), helped them ask providers informed questions (45% vs. 36%), and better prepared them to sign consent forms (46% vs. 37%). Overall, 63% of providers felt that the media platform improved patient learning, made patients more accountable, and standardized information dissemination. CONCLUSION(S): The EngagedMD media platform improves patient knowledge, satisfaction, and control over medical decision making and better prepares patients to give informed consent. Furthermore, it is well-liked by providers and is easily implemented.