A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.

The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.

The potential for Scotch Malt Whisky flavour diversification by yeast.

Scotch Whisky, a product of high importance to Scotland, has gained global approval for its distinctive qualities derived from the traditional production process, which is defined in law. However, ongoing research continuously enhances Scotch Whisky production and is fostering a diversification of flavour profiles. To be classified as Scotch Whisky, the final spirit needs to retain the aroma and taste of 'Scotch'. While each production step contributes significantly to whisky flavour-from malt preparation and mashing to fermentation, distillation, and maturation-the impact of yeast during fermentation is crucially important. Not only does the yeast convert the sugar to alcohol, it also produces important volatile compounds, e.g. esters and higher alcohols, that contribute to the final flavour profile of whisky. The yeast chosen for whisky fermentations can significantly influence whisky flavour, so the yeast strain employed is of high importance. This review explores the role of yeast in Scotch Whisky production and its influence on flavour diversification. Furthermore, an extensive examination of nonconventional yeasts employed in brewing and winemaking is undertaken to assess their potential suitability for adoption as Scotch Whisky yeast strains, followed by a review of methods for evaluating new yeast strains.

Introduction of the day case total laparoscopic hysterectomy (TLH) protocol.

BACKGROUND: Traditionally total laparoscopic hysterectomy (TLH) patients are admitted for 1-2 days post-operatively. Day case TLH has been proven to be feasible and safe in other countries; however, this tertiary Queensland hospital is one of the first Australian institutions to introduce a day case TLH protocol. AIM: To pilot the implementation of our day case TLH protocol assessing the feasibility, safety and patient satisfaction of same-day discharge. MATERIALS AND METHODS: A retrospective audit of the implementation of our day case TLH protocol at a tertiary Queensland hospital was conducted. Primary outcome was length of post-operative hospital stay. Secondary outcomes included perioperative complications and post-operative re-presentation rates. Patient satisfaction was assessed through a patient questionnaire. RESULTS: Seventy-seven patients were included in the study. There were 94.81% patients who went home on the same day. Their average length of post-operative hospital stay was 7.72 (SD ± 3.36) hours. Of the patients who did achieve same-day discharge, the average length of stay was 7.05 (SD ±1.46) hours. There were no significant differences in perioperative complications or re-presentation rates compared to previously published literature. Patients reported they were extremely satisfied with day case TLH. CONCLUSION: The implementation of our day case TLH protocol is feasible, safe and well received by patients in our tertiary Australian hospital. These results can have multimodal effects in healthcare: decrease in hospital costs by reducing length of stay and overnight admissions, improved theatre efficiency and patient flow, while maintaining patient safety and satisfaction.

Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial.

PURPOSE: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA. PATIENTS AND METHODS: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months. RESULTS: From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m2. Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively. CONCLUSION: Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups. TRIAL REGISTRATION: U.S. National Library of Medicine, NCT01686126.

Murine dorsal hair type is genetically determined by polymorphisms in candidate genes that influence BMP and WNT signalling.

Mouse dorsal coat hair types, guard, awl, auchene and zigzag, develop in three consecutive waves. To date, it is unclear if these hair types are determined genetically through expression of specific factors or can change based on their mesenchymal environment. We undertook a novel approach to this question by studying individual hair type in 67 Collaborative Cross (CC) mouse lines and found significant variation in the proportion of each type between strains. Variation in the proportion of zigzag, awl and auchene, but not guard hair, was largely due to germline genetic variation. We utilised this variation to map a quantitative trait locus (QTL) on chromosome 12 that appears to influence a decision point switch controlling the propensity for either second (awl and auchene) or third wave (zigzag) hairs to develop. This locus contains two strong candidates, Sostdc1 and Twist1, each of which carry several ENCODE regulatory variants, specific to the causal allele, that can influence gene expression, are expressed in the developing hair follicle, and have been previously reported to be involved in regulating human and murine hair behaviour, but not hair subtype determination. Both of these genes are likely to play a part in hair type determination via regulation of BMP and/or WNT signalling.

Investigating women with postmenopausal bleeding: The utility of endometrial thickness in transvaginal ultrasound.

BACKGROUND: Australian clinical guidelines recommend further investigation in females with postmenopausal bleeding (PMB) and endometrial thickness (ET) of ≥4 mm on transvaginal ultrasound (TVUS). However, the literature indicates that an ET of ≥3 mm as an upper limit is a more sensitive predictor of endometrial malignancy (EM) in females with PMB. AIMS: To assess whether Australian guidelines for PMB with an upper limit of 4 mm ET on ultrasound investigation, is sensitive enough for malignancy detection. MATERIAL AND METHODS: A retrospective study was performed on tissue results in PMB presentations to the Gold Coast Hospital and Health Service between 2011 and 2015. RESULTS: Twenty point nine percent of women with PMB had a malignancy. With an upper limit of 4 mm in ET on ultrasound, malignancy was present in 22% of participants. [Correction added on 10 July 2020, after first online publication: percentage of women with PMB that had a malignancy has been amended to twenty point nine percent.] CONCLUSIONS: A limit of 3 mm for ET in PMB, along with office endometrial biopsy, should be considered to ensure timely diagnoses.

Advances in yeast alcoholic fermentations for the production of bioethanol, beer and wine.

Yeasts have a long-standing relationship with humankind that has widened in recent years to encompass production of diverse foods, beverages, fuels and medicines. Here, key advances in the field of yeast fermentation applied to alcohol production, which represents the predominant product of industrial biotechnology, will be presented. More specifically, we have selected industries focused in producing bioethanol, beer and wine. In these bioprocesses, yeasts from the genus Saccharomyces are still the main players, with Saccharomyces cerevisiae recognized as the preeminent industrial ethanologen. However, the growing demand for new products has opened the door to diverse yeasts, including non-Saccharomyces strains. Furthermore, the development of synthetic media that successfully simulate industrial fermentation medium will be discussed along with a general overview of yeast fermentation modeling.

Potent and selective bivalent inhibitors of BET bromodomains.

Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments. The bivalent binding results in very high cellular potency for BRD4 binding and pharmacological responses such as disruption of BRD4-mediator complex subunit 1 foci with an EC50 of 100 pM. These compounds will be of considerable utility as BET/BRD4 chemical probes. This work illustrates a novel concept in ligand design-simultaneous targeting of two separate domains with a drug-like small molecule-providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins.

Enhancing Yeast Alcoholic Fermentations.

The production of ethanol by yeast fermentation represents the largest of all global biotechnologies. Consequently, the yeast Saccharomyces cerevisiae is the world's premier industrial microorganism, which is responsible not only for the production of alcoholic beverages, including beer, wine, and distilled spirits, but also for the billions of liters of bioethanol produced annually for use as a renewable transportation fuel. Although humankind has exploited the fermentative activities of yeasts for millennia, many aspects of alcohol fermentation remain poorly understood. This chapter will review some of the key considerations in optimizing industrial alcohol fermentations with a particular emphasis on enhancement opportunities involving cell physiology and strain engineering of the major microbial ethanologen, the yeast S. cerevisiae.

Borderline Ovarian Tumors: Fifteen Years' Experience at a Scottish Tertiary Cancer Center.

OBJECTIVES: Since the recognition of borderline ovarian tumors (BOTs) in the 1970s, the management of this subset of epithelial ovarian tumors has presented a challenge to clinicians. The majority present at an early stage, but their diagnosis is often only made following surgery, hence the heterogeneity of surgical management. Borderline ovarian tumors are morphologically diverse, and their behavior is subsequently also heterogeneous. We aimed to assess recurrence rates and the rate of malignant transformation in patients diagnosed with BOT. Secondary objectives included a review of current management and assessment of tumor markers, stage, cyst dimensions, and the presence of micropapillary features as prognostic indicators of recurrence. METHODS: This retrospective cohort study included all patients treated with BOT between 2000 and 2015 in the southeast region of Scotland. Clinical, surgicopathological, and follow-up data were collated. Data were analyzed with reference to recurrence and malignant transformation. RESULTS: Two hundred seventy-five patients underwent treatment for BOT in the study period. Surgical management was highly variable. A diagnosis of recurrent/persistent BOT or ovarian malignancy following initial treatment of BOT was rare, with only 12 (4%) of 275 cases. There were 7 cases (3%) of ovarian malignancy. Advanced International Federation of Gynecology and Obstetrics stage was the most prominent prognostic factor. Elevated preoperative serum CA-125 and the presence of micropapillary features correlated with advanced stage at presentation. With a lack of clear guidance, follow-up was highly variable with a median of 43 months (0-136 months). CONCLUSIONS: To our knowledge, this study is the largest BOT cohort in the United Kingdom. Recurrent disease is rare in optimally staged, completely resected, early-stage BOT, without high-risk features. Caution is needed in women electing not to undergo completion staging after diagnosis and in those opting for a fertility-preserving approach. Thorough informed consent and clear plans for surveillance and follow-up are needed with consideration of delayed completion surgery as appropriate.

Further assessment of exome-wide UVR footprints in melanoma and their possible relevance.

C>T substitutions at dipyrimidine sites dominate the melanoma genome. We recently analyzed the exomes of spontaneous and neonatal UVR-induced murine melanomas, noting a dramatic change in the genomic footprint at C>T substitutions in the latter. Here we re-analyzed published exome-wide footprints in human melanomas stratified in terms of likely previous sun exposure. Acral and mucosal melanomas were heterogeneous in terms of base substitution types, but most C>Ts occurred in the context of 3'G, probably resulting from spontaneous deamination of the cytosine. C>Ts in sun-exposed melanomas were statistically different from acral/mucosal lesions only in preferring an adjacent 5'T and 3'C. Pyrimidine dimer adducts can form between any pyrimidine (TT, TC, CT, CC). Hence in melanoma C>Ts are overwhelmingly induced at TC or CC photoproducts, or, there are peculiarities in DNA repair that favor the mutation of cytosines with these two pyrimidines adjacent. If melanoma UVR footprints at C>Ts reflect a specific dimer type (eg, 6-4 photoproduct or cyclobutane pyrimidine dimer), these could be removed post UVR, for instance using photolyases, to potentially reduce melanoma risk. If specific modes of DNA repair and/or replication cause these footprints, methodically downregulating selected DNA polymerases in UVR-induced animal models of melanoma, combined with exome sequencing, could begin to assess this. Finally, a preponderance of TpCpC as opposed to NpCpG at C>Ts exome-wide is likely to be a good indicator of whether a melanoma has incurred even a small amount of sun damage. This information will assist epidemiological studies in predicting individual levels of sun exposure.

The shift toward neo-adjuvant chemotherapy and interval debulking surgery for management of advanced ovarian and related cancers in a population-based setting: Impact on clinical outcomes.

OBJECTIVES: The aim of this study was to determine the proportion of patients with advanced ovarian and related cancers (EOC+RC), treated with neoadjuvant chemotherapy and interval debulking surgery (NACT - IDS), and to determine if there was any relationship with optimal cytoreduction rates and overall survival (OS) in a state-wide gynaecologic oncology service over time. METHODS: A retrospective review was undertaken using a population-based database of patients with stages 3 and 4 EOC+RC treated from 1982 till 2013 at the Queensland Centre for Gynaecological Cancer (QCGC). The proportion of patients treated with NACT - IDS compared with primary debulking surgery (PDS) was determined and compared with debulking rates and with the moving five-year OS probability. RESULTS: From 1982-2013, 2601 patients with advanced EOC+RC were managed at QCGC. No patients received NACT - IDS till 1995 when the first two patients received this treatment, rising to 55% of patients in 2013. Surgical cytoreduction rates to no macroscopic residual (R0) were achieved 32% of the time by 2006, rising to 48% in 2009, and 62% in 2013. Despite the increase in utilisation of NACT - IDS, our unit has noted a continued rise in the OS probability at five years to 45%. CONCLUSIONS: The increasing utilisation of NACT - IDS in the setting of a large centralised clinical service has been associated with increasing rates of optimal cytoreduction and survival rates have continued to rise in excess of those achieved in the trials reported to date.

Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free Survival Among Women With Stage I Endometrial Cancer: A Randomized Clinical Trial.

Importance: Standard treatment for endometrial cancer involves removal of the uterus, tubes, ovaries, and lymph nodes. Few randomized trials have compared disease-free survival outcomes for surgical approaches. Objective: To investigate whether total laparoscopic hysterectomy (TLH) is equivalent to total abdominal hysterectomy (TAH) in women with treatment-naive endometrial cancer. Design, Setting, and Participants: The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a multinational, randomized equivalence trial conducted between October 7, 2005, and June 30, 2010, in which 27 surgeons from 20 tertiary gynecological cancer centers in Australia, New Zealand, and Hong Kong randomized 760 women with stage I endometrioid endometrial cancer to either TLH or TAH. Follow-up ended on March 3, 2016. Interventions: Patients were randomly assigned to undergo TAH (n = 353) or TLH (n = 407). Main Outcomes and Measures: The primary outcome was disease-free survival, which was measured as the interval between surgery and the date of first recurrence, including disease progression or the development of a new primary cancer or death assessed at 4.5 years after randomization. The prespecified equivalence margin was 7% or less. Secondary outcomes included recurrence of endometrial cancer and overall survival. Results: Patients were followed up for a median of 4.5 years. Of 760 patients who were randomized (mean age, 63 years), 679 (89%) completed the trial. At 4.5 years of follow-up, disease-free survival was 81.3% in the TAH group and 81.6% in the TLH group. The disease-free survival rate difference was 0.3% (favoring TLH; 95% CI, -5.5% to 6.1%; P = .007), meeting criteria for equivalence. There was no statistically significant between-group difference in recurrence of endometrial cancer (28/353 in TAH group [7.9%] vs 33/407 in TLH group [8.1%]; risk difference, 0.2% [95% CI, -3.7% to 4.0%]; P = .93) or in overall survival (24/353 in TAH group [6.8%] vs 30/407 in TLH group [7.4%]; risk difference, 0.6% [95% CI, -3.0% to 4.2%]; P = .76). Conclusions and Relevance: Among women with stage I endometrial cancer, the use of total abdominal hysterectomy compared with total laparoscopic hysterectomy resulted in equivalent disease-free survival at 4.5 years and no difference in overall survival. These findings support the use of laparoscopic hysterectomy for women with stage I endometrial cancer. Trial Registration: clinicaltrials.gov Identifier: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516.

Use of thermo-coagulation as an alternative treatment modality in a 'screen-and-treat' programme of cervical screening in rural Malawi.

The incidence of cervical cancer in Malawi is the highest in the world and projected to increase in the absence of interventions. Although government policy supports screening using visual inspection with acetic acid (VIA), screening provision is limited due to lack of infrastructure, trained personnel, and the cost and availability of gas for cryotherapy. Recently, thermo-coagulation has been acknowledged as a safe and acceptable procedure suitable for low-resource settings. We introduced thermo-coagulation for treatment of VIA-positive lesions as an alternative to cryotherapy within a cervical screening service based on VIA, coupled with appropriate, sustainable pathways of care for women with high-grade lesions and cancers. Detailed planning was undertaken for VIA clinics, and approvals were obtained from the Ministry of Health, Regional and Village Chiefs. Educational resources were developed. Thermo-coagulators were introduced into hospital and health centre settings, with theoretical and practical training in safe use and maintenance of equipment. A total of 7,088 previously unscreened women attended VIA clinics between October 2013 and March 2015. Screening clinics were held daily in the hospital and weekly in the health centres. Overall, VIA positivity was 6.1%. Almost 90% received same day treatment in the hospital setting, and 3- to 6-month cure rates of more than 90% are observed. Thermo-coagulation proved feasible and acceptable in this setting. Effective implementation requires comprehensive training and provider support, ongoing competency assessment, quality assurance and improvement audit. Thermo-coagulation offers an effective alternative to cryotherapy and encouraged VIA screening of many more women.

Hair follicle melanocyte precursors are awoken by ultraviolet radiation via a cell extrinsic mechanism.

Melanocyte stem cells (MCSCs) in the upper portion of the hair follicle periodically supply melanocytes (MCs) that migrate downward into the hair bulb during anagen, the growth phase of the hair cycle. However MCs can also migrate upwards. We previously observed an increase in epidermal MC density in the mouse epidermis after a single ultraviolet radiation (UVR) exposure in neonatal, but not adult mice. To better understand MCSC activation by UVR we methodically studied the response of MCs to narrow band UVB (since UVA does not invoke this response) exposure in neonatal mice, and in adults at different stages of the hair cycle. We found that a single exposure of adult mice did not induce activation of MCSCs, in any stage of the hair cycle. When adult mice MCSCs were isolated in telogen, multiple UVB exposures resulted in their activation and production of daughter cells, which migrated upwards to the epidermis. Importantly, the MCSCs produced new progeny without themselves having incurred DNA damage after UVB exposure. This, together with examination of MC localisation in the skin of mice overexpressing stem cell factor in their keratinocytes, leads us to conclude that MCSC activation by UVB is driven via paracrine production of either SCF and/or other keratinocyte cytokines. We re-examined the increase in epidermal MC density in neonatal mouse skin. This effect was much more profound after only a single exposure than that of even multiple exposures to adult skin, and we show that in this setting also, the epidermal MCs mostly derive from activation of MC precursors in the upper hair follicle, and most likely via a cell extrinsic mechanism. Hence, although adaptive changes in the skin induced by repetitive UVB exposures are necessary in adult mice, in both the adult and neonatal context the division and migration upwards of follicular MCSCs is the major mode by which epidermal MC numbers increase after UVR exposure.

From intramural ectopic pregnancy to hysterectomy: A case report.

An intramural ectopic pregnancy is one of the rarest types of ectopic pregnancy, and due to the scarcity of reported cases there are no clear guidelines regarding diagnosis and management of the condition. We report a case of a non-viable intramural ectopic pregnancy managed with intravenous methotrexate, in a patient with no previous pregnancies but a history of uterine cornual cyst excision. The patient subsequently developed a uterine arteriovenous malformation, which was embolised. Following this, she had two pregnancies, one culminating in an elective caesarean section at term, and the other a medical termination of pregnancy at 19 weeks of gestation. As a result of post-traumatic stress disorder attributed to this complicated history, the patient requested a hysterectomy. This case demonstrates the complexity of the management of intramural ectopic pregnancy and highlights the impacts the condition can have on a patient's physical and mental health.

Early endovascular retrieval of a migrated Implanon NXT from a branch of the right pulmonary artery.

A woman in her 20s was referred to a tertiary hospital emergency department for management of a migrating Implanon NXT. The Implanon was inserted 1 week prior by the patient's general practitioner who was unable to palpate the Implanon after insertion and hence, ordered an ultrasound scan which showed an actively migrating Implanon in the left basilic vein. She had mild chest pain, and her physical examination, ECG and blood tests were unremarkable. A CT chest showed a 31 mm foreign body within the right lower lobar artery. The foreign body was removed by interventional radiology by accessing the right internal jugular vein under ultrasound guidance and inserting a 6 FR pig catheter into the pulmonary trunk. The position was confirmed with angiogram and the foreign body was removed using a goose neck snare. The patient was discharged the same day with no complications, and fell pregnant a few months afterwards.

Adhesion barriers in gynecologic surgeries and cesarean section: An Asia-Pacific expert panel consensus recommendation.

Adhesions arising from gynecologic surgeries and cesarean sections pose substantial clinical, social, and economic challenges, leading to issues like pelvic pain, infertility, bowel obstruction, and recurring surgeries. Preventing adhesions is a pressing unmet need, hindered by difficulties in assessing postoperative adhesions and understanding barriers. To bridge adhesion prevention gaps, statements on clinical practices were synthesized to present Asia-Pacific expert perspectives on gynecologic surgery and cesarean section adhesion prevention. An expert panel of eight physicians from various healthcare settings in the Asia-Pacific region was convened and a comprehensive literature search on topics related to adhesion prevention in gynecologic surgeries and cesarean sections was performed. Information from full-text publications was used to develop draft consensus statements, with each statement assigned the highest available evidence level based on a systematic literature review and graded using the Oxford Center for Evidence-based Medicine criteria. A modified Delphi process, involving two rounds of online voting and discussions with an extended group of 109 experts, was employed to reach a consensus on six topics related to adhesion barriers. A set of 15 consensus statements were synthesized. Key topics include adhesion incidence in Asia, cesarean section complications, barrier application status, adhesion formation and prevention, absorbable barriers' effectiveness, recommendations, and future considerations. The statements provide guidance for healthcare professionals, especially in the Asia-Pacific region, to tackle the challenges posed by postoperative adhesions and improve patient outcomes. Further research is needed to enhance understanding and prevention of adhesions in this region.

Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer.

Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.