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BackgroundMedian overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.Patients and methodsExpression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.ResultsExpression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years.ConclusionThe OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

BackgroundMucormycosis is a deadly fungal infection that mainly affects severely immunocompromised patients. We report herein the case of a previously immunocompetent adult woman who developed invasive cutaneous mucormycosis after severe burn injuries. Interferon-gamma (IFN-γ) treatment was added after failure of conventional treatment and confirmation of a sustained profound immunodepression. The diagnosis was based on a reduced expression of HLA-DR on monocytes (mHLA-DR), NK lymphopenia and a high proportion of immature neutrophils. The immune-related alterations were longitudinally monitored using panels of immune-related biomarkers.ResultsInitiation of IFN-γ was associated with a rapid clinical improvement and a subsequent healing of mucormycosis infection, with no residual fungi at the surgical wound repair. The serial immunological assessment showed sharp improvements of immune parameters: a rapid recovery of mHLA-DR and of transcriptomic markers for T-cell proliferation. The patient survived and was later discharged from the ICU.ConclusionThe treatment with recombinant IFN-γ participated to the resolution of a progressively invasive mucormycosis infection, with rapid improvement in immune parameters. In the era of precision medicine in the ICU, availability of comprehensive immune monitoring tools could help guiding management of refractory infections and provide rationale for immune stimulation strategies in these high risk patients.

Klinefelter syndrome is the most prevalent chromosome disorder in infertile men, characterized by one or more additional X chromosomes. This manuscript reviews the spectrum of phenotypic variability, testicular histopathology and hormonal imbalances associated with Klinefelter syndrome across different developmental stages from infancy through adulthood. Klinefelter syndrome typically manifests with small firm testes, azoospermia, hypergonadotrophic hypogonadism and a tall feminine stature. Testicular biopsies reveal progressive germ cell depletion, seminiferous tubule hyalinization, testicular fibrosis and Leydig cell hyperplasia, contributing to elevated luteinizing hormone and follicle stimulating hormone levels alongside decreased inhibin B and anti-Müllerian hormone levels from mid-puberty onwards. Despite extensive research, the exact mechanisms underlying these changes remain unclear, highlighting the need for further investigation to enhance diagnostic accuracy and therapeutic outcomes for Klinefelter individuals, especially in fertility preservation and restoration strategies. [ABSTRACT FROM AUTHOR]

Due to the growing number of young patients at risk of germ cell loss, there is a need to preserve spermatogonial stem cells for patients who are not able to bank spermatozoa. Worldwide, more and more clinics are implementing testicular tissue (TT) banking programs, making it a novel, yet indispensable, discipline in the field of fertility preservation. Previously, TT cryopreservation was predominantly offered to young cancer patients before starting gonadotoxic chemo- or radiotherapy. Nowadays, most centers also bank TT from patients with non-malignant conditions who need gonadotoxic conditioning therapy prior to hematopoietic stem cell (HSCT) or bone marrow transplantation (BMT). Additionally, some centers include patients who suffer from genetic or developmental disorders associated with prepubertal germ cell loss or patients who already had a previous round of chemo- or radiotherapy. It is important to note that the surgical removal of TT is an invasive procedure. Moreover, TT cryopreservation is still considered experimental as restoration methods are not yet clinically available. For this reason, TT banking should preferably only be offered to patients who are at significant risk of becoming infertile. In our view, TT cryopreservation is recommended for young cancer patients in need of high-risk chemo- and/or radiotherapy, regardless of previous low-risk treatment. Likewise, TT banking is advised for patients with non-malignant disorders such as sickle cell disease, beta-thalassemia, and bone marrow failure, who need high-risk conditioning therapy before HSCT/BMT. TT retrieval during orchidopexy is also proposed for patients with bilateral cryptorchidism. Since patients with a medium- to low-risk treatment generally maintain their fertility, TT banking is not advised for this group. Also for Klinefelter patients, TT banking is not recommended as it does not give better outcomes than a testicular sperm extraction later in life.

Human health biobanks are forms of research infrastructure that supply biospecimens and associated data to researchers, and therefore juxtapose the activities of clinical care and biomedical research. The discipline of biobanking has existed for over 20 years and is supported by several international professional societies and dedicated academic journals. However, despite both rising research demand for human biospecimens, and the growth of biobanking as an academic discipline, many individual biobanks continue to experience sustainability challenges. This commentary will summarize how the COVID-19 pandemic is creating new challenges and opportunities for both the health biobanking sector and the supporting discipline of biobanking. While the challenges for biobanks may be numerous and acute, there are opportunities for both individual biobanks and the discipline of biobanking to embrace change such that biobanks can continue to support and drive biomedical research. We will therefore describe numerous practical steps that individual biobanks and/or the discipline of biobanking can take to survive and possibly thrive in response to the COVID-19 pandemic.

Transcription is a stochastic process occurring mostly in episodic bursts. Although the local chromatin environment is known to influence the bursting behavior on long timescales, the impact of transcription factors (TFs)--especially in rapidly inducible systems--is largely unknown. Using fluorescence in situ hybridization and computational models, we quantified the transcriptional activity of the proto-oncogene c-Fos with single mRNA accuracy at individual endogenous alleles. We showed that, during MAPK induction, the TF concentration modulates the burst frequency of c-Fos, whereas other bursting parameters remain mostly unchanged. By using synthetic TFs with TALE DNA-binding domains, we systematically altered different aspects of these bursts. Specifically, we linked the polymerase initiation frequency to the strength of the transactivation domain and the burst duration to the TF lifetime on the promoter. Our results show how TFs and promoter binding domains collectively act to regulate different bursting parameters, offering a vast, evolutionarily tunable regulatory range for individual genes.

We discuss two electrochemical plating approaches for nanotwinned copper (ECP nt-Cu)--Gen 1 and Gen 2. These two approaches allow control over columnar width and transition layer thickness on Cu substrates, enabling the filling of nanotwinned Cu for bonding applications. Both approaches produce stable nt-Cu structures with minimal transition layers when electroplated on (111) Cu substrate. However, grain size, transition layer thickness on polycrystalline substrates, and feature-filling behavior differ. The researchers suggest that the choice between Gen 1 and Gen 2 depends on the feature size, aspect ratio, and applications. In addition, further exploration into other additives improves bottom-up filling capabilities, enabling more versatility for applications. Both approaches enable the filling of nanotwinned Cu inside bottom-seeded and complete-seeded features, with 100% nanotwin growth parallel to the substrate for bottomseeded features. However, nanotwin growth percentage and direction depend on feature size and aspect ratio for complete-seeded features. Gen 2 tends to have less sidewall growth due to its smaller grain size and is more compatible with other additives, making it promising for high aspect ratio small features. [ABSTRACT FROM AUTHOR]

Young boys undergoing gonadotoxic treatments are at high risk of spermatogonial stem cell (SSC) loss and fertility problems later in life. Stem cell loss can also occur in specific genetic conditions, eg, Klinefelter syndrome (KS). Before puberty, these boys do not yet produce sperm. Hence, they cannot benefit from sperm banking. An emerging alternative is the freezing of testicular tissue aiming to preserve the SSCs for eventual autologous transplantation or in vitro maturation at adult age. Many fertility preservation programmes include cryopreservation of immature testicular tissue, although the restoration procedures are still under development. Until the end of 2018, the Universitair Ziekenhuis Brussel has frozen testicular tissues of 112 patients between 8 months and 18 years of age. Testicular tissue was removed in view of gonadotoxic cancer treatment (35%), gonadotoxic conditioning therapy for bone marrow transplantation (35%) or in boys diagnosed with KS (30%). So far, none of these boys had their testicular tissue transplanted back. This article summarizes our experience with cryopreservation of immature testicular tissue over the past 16 years (2002-2018) and describes the key issues for setting up a cryopreservation programme for immature testicular tissue as a means to safeguard the future fertility of boys at high risk of SSC loss.