bluuebunny/crossref_metadata_2025_split huggingface dataset:
National Ovarian and Testicular Tissue Transport and Cryopreservation Service (NOTTCS)
Authors: MARTIN Andrea , TORO Marcela , ROZEN Genia , AGRESTA Franca , GOOK Debra , STERN Kate 
Published: November 2022

Background: Recognised female fertility preservation strategies include oocyte and embryo cryopreservation. Ovarian tissue cryopreservation is no longer experimental, and the only option for children and pre-pubertal girls. Although testicular cryopreservation remains experimental for boys, it has the potential to evolve and provide a realistic opportunity for fertility in the future. The RWH/MIVF fertility preservation service has been preserving ovarian tissue since 1995. This service has been available to children, adolescent young adults (AYA) and adults about to receive gonadotoxic treatment for malignant and non-malignant conditions. In 2013, this service was extended to freezing testicular tissue for pre-pubertal and peri-pubertal males. Until 2019 these fertility preservation options have only been available to those undergoing procedures at Melbourne metropolitan hospitals. Young cancer patients seeking fertility preservation in regional or interstate areas, did not have this opportunity due to lack of access and resources. One approach to increasing patient access to Gonadal Tissue Cryopreservation (GTC), was to establish a national tissue retrieval and transport service. Aim: This paper describes the uptake of a GTC transport program at RWH, allowing rural and interstate oncology referral for transport, processing and storage of gonadal tissue in an acknowledged centre of excellence. Method: An information/education/instruction resource package was developed for fertility units Australia-wide, supported by a centralised GTC program coordinator. Referrals are fast tracked to eliminate any delay in treatment. Gonadal tissue is harvested at the referring hospital and transported to RWH for cryopreservation and storage, following methods established in other countries with a centralised service 1 – 3 . Results: To date, 40 ovarian and testicular tissue has been transported from all Australian states, and Northern Territory to RWH, including semen transported from a regional hospital where no fertility service was available. This service was made possible, and free of charge to those patients 13–30 yo with a cancer diagnosis, through a generous donation by Sony Foundation. Conclusion: Provision of a comprehensive fertility preservation service, including GTC, for young people, was not widely available until 2019. Gonadal tissue transport facilitates engagement and upskilling in oncofertility with extensive support from a centre of excellence, allowing expansion of patient and provider access to best-practice fertility preservation options, regardless of their geographic location and socio-economic status.
Can we Make SpermFAST? Improving Sperm Function to Increase Fertilisation Rates after in vitro Fertilisation
Authors: MCPHERSON Nicole O. , HAMILTON Hamish , ZANDER-FOX Deirdre , ARCHER Emily , BAKOS Hassan W. 
Published: November 2022

Background: Intracytoplasmic sperm injection (ICSI) usage ([Formula: see text]64% of autologous cycles) has increased in Australia as an attempt to avoid low fertilisation and total fertilisation failure after standard in vitro fertilization (IVF). ICSI and to a lesser extent IVF, bypass key sperm maturation (hyperactivation, capacitation/acrosome reaction) events that naturally occur in the female tract and are vital for successful fertilisation. Current commercial sperm preparation media are not fully designed to induce these changes in sperm prior to insemination. Aim: To improve fertilisation rates following IVF by increasing sperm capacitation and hyperactivation between sperm preparation and insemination ultilising a new sperm medium (SpermFAST). Method: Sperm from 12 consenting normospermic men were incubated in either G-IVF+ (Vitrolife) or SpermFAST (UoA/Monash IVF) following a direct swim-up. Measures of capacitation, hyperactivation, sperm binding, acrosome reaction and oxidative DNA damage were assessed. Further, sperm from male CBAF1 mice (N=8) were incubated in either G-IVF+ or SpermFAST prior to IVF insemination. Fertilisation rates, embryo development, blastocyst cell numbers and DNA damage were assessed. Results: Incubation of human sperm in SpermFAST increased tyrosine phosphorylation (15.8% vs 9.5%, P[Formula: see text]0.05), hyperactive motility (38.3% vs 14.9%, P[Formula: see text]0.01), sperm binding (73.1% vs 47.7%, P[Formula: see text]0.01), while having no impact on sperm acrosomal status or oxidative DNA damage levels. Following IVF in the mouse, sperm incubated in SpermFAST increased fertilisation rates (94% vs 88%, P[Formula: see text]0.05), blastocyst total cell (92.2% vs 77.4%, P[Formula: see text]0.05), inner cell mass (14.9% vs 18.9%, P[Formula: see text]0.01) and epiblast cell numbers (3.7% vs 1.6%, P[Formula: see text]0.01), while the proportion of DNA damaged cells decreased in blastocysts (2.3% vs 4.8%, P[Formula: see text]0.001). Conclusion: Sperm function and fertilisation rates are improved when the sperm medium better mimics the environment of the female reproductive tract during natural conception. Improving IVF culture media to better meet the physiological needs of sperm could potentially improve outcomes following IVF.
Diet, Fertility and the Australian Primary Health Care Setting — A Review
Authors: PANDELIOS Georgia , LAWS Rachel , MORAN Lisa , CAMPBELL Karen 
Published: November 2022

Background: The relationship between diet and fertility continues to emerge, yet interventions underutilise this evidence within Australian primary health care (PHC). Infertility affects approximately 9% of the world’s population and 16% of Australian couples trying to conceive naturally. Current PHC practices do not address nor encourage improved diet for sperm and oocyte quality, ovulation and sperm production. Due to a lack of resources and training, general practitioners typically refer these individuals to fertility clinics for medical management. As a result, Australia ranks as the 6th highest global utiliser of assisted reproductive technology, with annual costs to treat infertility exceeding $46,000,000. Aim: To synthesise current evidence for the diet-fertility relationship and identify suitable PHC interventions for improving fertility related lifestyle risk factors. Method: A database search for published peer reviewed articles using MEDLINE, Scopus, Google Scholar, PubMed and Global Health was carried out, and narratively synthesised. Results: Poor diet, central adiposity and unhealthy weight are modifiable risk factors impacting fertility, and common amongst the Australian adult population. There are opportunities to address these risk factors by modifying existing lifestyle modification programs to improve the overall fertility profile of this demographic within PHC. Conclusion: It is possible to optimise fertility through lifestyle interventions that encompass dietary modification. Health and fertility treatment costs can potentially be improved if changes to diet and lifestyle are consistently addressed as first line management for infertility within PHC for appropriate individuals. Understanding evidence for interventions have importuning implications for policy and practice. Further work needs to describe how fertility lifestyle interventions can successfully translate into PHC practice.
Psychological Evaluation of Women with Absolute Uterine Infertility Prior to the Introduction of Uterus Transplantation
Authors: PITTMAN Jana , MORRISON Natalie , MOGENSEN Lise , DEANS Rebecca 
Published: November 2022

Background: Uterus transplantation may offer women with absolute uterine infertility the chance for gestational motherhood. Infertility treatment can be associated with psychological distress and the absolute nature of infertility in these women could heighten the risk. While uterus transplantation is promising the potential repercussion of graft failure and organ availability could have repercussions on these families. Understanding the baseline psychological well-being prior to uterus transplant is needed to support these women. Aim: Explore baseline psychological scores in women with acquired and congenital uterine absence. Method: A survey including demographic data and two-validated tools, DASS21 and FertiQOL was given to two groups, women with congenital uterine absence and those with acquired (hysterectomy). Data was compared between groups for DASS21, and against Boivin et al. 1 normative data for women with infertility (FertiQOL). Results: The study included 41 women, (average age 32.6yrs ± 10.4). As a collective only moderate depression, mild anxiety, and mild stress scores were reported however in the congenital uterine absence group 10.5% reported extremely severe anxiety and 5.3% extreme depression. Mean FertiQOL score was 57.76, 3.16 points higher than Boivin’s average. Women with hysterectomy scored on average 15.36 points lower than those with congenital uterine absence. Conclusion: In this study, women with congenital uterine infertility appeared to experience significantly higher levels of depression and anxiety than women post-hysterectomy. The opposite was seen in infertility scores where women with congenital absence reported higher quality of life scores than both the normative values and those post-hysterectomy. It is essential robust psychological screening and support is offered to these women prior to inclusion into a uterus transplant program.
“Thick and Viscous” or “Light and Easy”: An Oil Overlay Comparison
Authors: GUNASEGARAN Kavyadharshini , DEAN Casey , GABRIEL Justine , SORBY Kelli 
Published: November 2022

Background: Oil overlay in IVF culture media is essential in the maintenance of pH and prevention of evaporation. The recent proliferation of “Heavy oil” raises questions of how oil density and viscosity affect CO2 diffusion into and out of culture media. Aim: To compare the effects of “Heavy oil” versus standard oil on pH stability in embryo culture dishes. Method: Density (g/ml) readings of each oil (Ovoil, Ovoil Heavy and LifeGuard) were obtained in triplicate using a volumetric flask and analytical balance in both refrigerated (4[Formula: see text]C) and warmed state (37[Formula: see text]C). Viscosity testing was performed externally by Intertek laboratory. pH was measured at regular intervals using a blood gas analyser (EPOC system) in culture dishes under standard and ‘Heavy’ oil overlays. Results: Density measurements showed Ovoil Heavy to be the least dense (0.8227g/ml) followed by Ovoil (0.8476g/ml), with LifeGuard the most dense at 0.8640g/ml. There was a significant difference (p<0.0001) when comparing densities between oil types in both 4[Formula: see text]C and 37[Formula: see text]C. Viscosity testing reported LifeGuard the most viscous at 153.6mm2/s followed by Ovoil Heavy at 57.98mm2/s and Ovoil at 30.68mm2/s. Media equilibrated more slowly under denser oil, requiring 5 hours to read pH 7.4 under LifeGuard with lighter oil requiring 3 hours to reach equilibration. Equilibrated dishes exposed to reduced CO2 concentration (4%) showed quicker pH loss in Ovoil at 0.049/hour when compared to LifeGuard at 0.034/hour (p=0.006). Culture dishes placed in a humidicrib with open cuffs, emulating real world settings, showed slower pH loss under LifeGuard (0.06/hour) compared to Ovoil (0.08/hour). Conclusion: Higher density oil overlay takes longer to equilibrate to optimal pH but can slow down loss of pH when dishes are exposed to ambient conditions.
Case Report: Ovarian Torsion Prior to Oocyte Trigger in a Woman Undergoing In Vitro Fertilisation
Authors: WARD Madeleine , CARTER Michael , POHL Nyssa , DALTON Russell , BARDSLEY Michael 
Published: November 2022

Background: Ovarian torsion accounts for 2.7% of the surgical emergencies in women 1 yet remains a morbid and frequently misdiagnosed condition 2 . Aim: Here we describe a case of ovarian torsion prior to administration of the trigger in a 35-year-old multigravida undergoing controlled ovarian stimulation on a background of bilateral salpingectomy, along with the outcome of post detorsion oocyte pick up. Result: An antagonist protocol was used with a follicular count on day 12 confirming eight follicles in each of the right and left ovaries. The day prior to the planned GnRH agonist trigger, she developed a sudden onset of severe abdominal pain associated with vomiting. Urgent laparoscopy demonstrated a 720-degree torsion of the right ovary, which was detorted without complication. The patient was discharged home on the same day, a trigger was administered, and oocyte retrieval completed as per schedule. Post torsion 11 oocytes were collected, four from the left and seven from the right, a final embryo cryopreservation rate of 57% from the affected right ovary compared with 50% from the left ovary was achieved. Conclusion: In vitro fertilisation is a recognised risk factor for ovarian torsion 2 . Here we report the first case of a torsion in a woman prior to the administration of a trigger, who successfully underwent detorsion with salvage of oocytes collection and embryo cryopreservation.
DuoStim: The Patient Experience of a Follicular and Luteal Phase Stimulation
Authors: WARD Madeleine , DALTON Russell , WOODS Glenda , DOWLING Katrina , POHL Nyssa 
Published: November 2022

Background: A dual stimulation, or ‘DuoStim’ protocol results in the recruitment of developing waves of antral follicles to occur one after the other within a menstrual cycle 1 . This proffers benefits for women who have previously demonstrated a poor response to assisted reproductive technologies, providing an opportunity to increase the number of oocytes collected, as well as for women aiming for fertility preservation 1 . Aim: We report on the experience of women who have undergone dual stimulation and oocyte pick up, in both the follicular and luteal phase of the cycle. Result: All women who underwent a DuoStim cycle at a single IVF centre in Victoria, Australia were invited to participate. Information was collected regarding experience and satisfaction across the domains of social, emotional, financial and alignment with fertility goals utilising a 5-point Likert Scale. Conclusion: Whilst dual stimulation protocols offer promising options for specific patient populations there remains a need to report on quality outcomes 2 .
Striving for Egg-Cellence: Step-by-Step Guide to Oocyte Pick Up
Authors: WARD Madeleine , BRENNAN Lachlan , BARDSLEY Michael , CARTER Michael , DALTON Russell 
Published: November 2022

Background: Oocyte pick up (OPU) involves the suction aspiration of ovarian follicles following controlled ovarian stimulation, via an ultrasound guided needle through the vaginal fornices 1 . There is international recognition of a lack of training tools in OPU, highlighting opportunity for technology and simulation to be further developed 1 . Aim: Here we provide a step-by-step approach to performing transvaginal ultrasound guided OPU with supporting video demonstration. Result: Interviews and procedural observation was undertaken with four fertility specialists performing OPU at a single IVF centre. Routine practice was combined with tips and tricks into a step-by-step guide to OPU. Step one covers procedural planning, patient identification and vaginal preparation. Step two discusses the gentle and steady techniques for optimal follicle aspiration, Step three highlights the important steps required for the care of the oocyte to ensure the best outcomes. Conclusion: A meticulous approach to the retrieval of oocyte is paramount to maintaining their quality; maximising training tools for technique is therefore essential 1 .
Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer
Authors: Goodwin Craig M. , Waters Andrew M. , Klomp Jennifer E. , Javaid Sehrish , Bryant Kirsten L. , Stalnecker Clint A. , Drizyte-Miller Kristina , Papke Bjoern , Yang Runying , Amparo Amber M. , Ozkan-Dagliyan Irem , Baldelli Elisa , Calvert Valerie , Pierobon Mariaelena , Sorrentino Jessica A. , Beelen Andrew P. , Bublitz Natalie , Lüthen Mareen , Wood Kris C. , Petricoin Emanuel F. , Sers Christine , McRee Autumn J. , Cox Adrienne D. , Der Channing J. 
Published: November 2022

Abstract

Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK–MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, antiapoptotic signaling, and MYC expression. On the basis of these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As inhibition of other proteins might also counter CDK4/6i-mediated signaling changes to increase cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function screen was conducted that revealed a spectrum of functionally diverse genes whose loss enhanced CDK4/6i growth inhibitory activity. These genes were enriched around diverse signaling nodes, including cell-cycle regulatory proteins centered on CDK2 activation, PI3K–AKT–mTOR signaling, SRC family kinases, HDAC proteins, autophagy-activating pathways, chromosome regulation and maintenance, and DNA damage and repair pathways. Novel therapeutic combinations were validated using siRNA and small-molecule inhibitor–based approaches. In addition, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to patients with PDAC.

Significance:
CRISPR-Cas9 screening and protein activity mapping reveal combinations that increase potency of CDK4/6 inhibitors and overcome drug-induced compensations in pancreatic cancer.
NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects
Authors: Belhadj Sami , Khurram Aliya , Bandlamudi Chaitanya , Palou-Márquez Guillermo , Ravichandran Vignesh , Steinsnyder Zoe , Wildman Temima , Catchings Amanda , Kemel Yelena , Mukherjee Semanti , Fesko Benjamin , Arora Kanika , Mehine Miika , Dandiker Sita , Izhar Aalin , Petrini John , Domchek Susan , Nathanson Katherine L. , Brower Jamie , Couch Fergus , Stadler Zsofia , Robson Mark , Walsh Michael , Vijai Joseph , Berger Michael , Supek Fran , Karam Rachid , Topka Sabine , Offit Kenneth 
Published: November 2022

Abstract

Purpose:
To explore the role of NBN as a pan-cancer susceptibility gene.

Experimental Design:
Matched germline and somatic DNA samples from 34,046 patients were sequenced using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and presumed pathogenic germline variants (PGV) identified. Allele-specific and gene-centered analysis of enrichment was conducted and a validation cohort of 26,407 pan-cancer patients was analyzed. Functional studies utilized cellular models with analysis of protein expression, MRN complex formation/localization, and viability assessment following treatment with γ-irradiation.

Results:
We identified 83 carriers of 32 NBN PGVs (0.25% of the studied series), 40% of which (33/83) carried the Slavic founder p.K219fs. The frequency of PGVs varied across cancer types. Patients harboring NBN PGVs demonstrated increased loss of the wild-type allele in their tumors [OR = 2.7; confidence interval (CI): 1.4–5.5; P = 0.0024; pan-cancer], including lung and pancreatic tumors compared with breast and colorectal cancers. p.K219fs was enriched across all tumor types (OR = 2.22; CI: 1.3–3.6; P = 0.0018). Gene-centered analysis revealed enrichment of PGVs in cases compared with controls in the European population (OR = 1.9; CI: 1.3–2.7; P = 0.0004), a finding confirmed in the replication cohort (OR = 1.8; CI: 1.2–2.6; P = 0.003). Two novel truncating variants, p.L19* and p.N71fs, produced a 45 kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity to γ-irradiation and lower levels of radiation-induced KAP1 phosphorylation.

Conclusions:
Burden analyses, biallelic inactivation, and functional evidence support the role of NBN as contributing to a broad cancer spectrum. Further studies in large pan-cancer series and the assessment of epistatic and environmental interactions are warranted to further define these associations.
ЗАСТОСУВАННЯ ГЕННОІНЖЕНЕРНИХ ЗАСОБІВ У ЛІКУВАННІ ХВОРИХ НА COVID-19
Authors: Москалюк В.Д. , Сирота Б.В. 
Published: November 2022

Однією з найбільш актуальних тем на сьогодні є коронавірусна інфекція, спричинена SARS-CoV-2, яка набула не тільки медичного, а й, безумовно, соціального значення. Всесвітньою організацією охорони здоров’я 11 березня 2020 р. оголошено пандемію COVID-19. Сучасні терапевтичні варіанти лікування COVID-19 поєднують застосування препаратів, що впливають як на сам вірус, так і на компоненти імунної відповіді організму. Незважаючи на те, що патогенетичні механізми інфекційного захворювання були частково досліджені, методи лікування все ще не виправдовують очікувань, що значною мірою зумовлено розвитком небажаних медикаментозних реакцій та суперечливими результатами лікування. Наразі, кількість експериментальних генно-інженерних молекул, запропонованих до лікування SARS-CoV-2, невпинно зростає, що зумовлює необхідність аналізу сучасних наукових джерел щодо перспектив, переваг та недоліків застосування віруснейтралізувальних моноклональних антитіл, натуральних кілерів, мезенхімальних стовбурових клітин і моноклональних антитіл до інтерлейкіну-6.
ДО 80-РІЧЧЯ АКАДЕМІКА НАН УКРАЇНИ І НАМН УКРАЇНИ, ПРОФЕСОРА В.П. ШИРОБОКОВА
Authors: Avtoriv Kolektyv 
Published: November 2022

Наведено біографічні дані й творчий доробок видатного українського мікробіолога В.П. Широбокова – доктора медичних наук, академіка НАН та НАМН України, професора, чия трудова діяльність нерозривно пов’язана протягом 57 років з Національним медичним університетом імені О.О. Богомольця, 42 з яких – у статусі завідувача кафедри.