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HORMAD1 expression is usually restricted to germline cells, but it becomes mis-expressed in epithelial cells in ~60% of triple-negative breast cancers (TNBCs), where it is associated with elevated genomic instability (1). HORMAD1 expression in TNBC is bimodal with HORMAD1-positive TNBC representing a biologically distinct disease group. Identification of HORMAD1-driven genetic dependencies may uncover novel therapies for this disease group. To study HORMAD1-driven genetic dependencies, we generated a SUM159 cell line model with doxycycline-inducible HORMAD1 that replicated genomic instability phenotypes seen in HORMAD1-positive TNBC (1). Using small interfering RNA screens, we identified candidate genes whose depletion selectively inhibited the cellular growth of HORMAD1-expressing cells. We validated five genes (ATR, BRIP1, POLH, TDP1 and XRCC1), depletion of which led to reduced cellular growth or clonogenic survival in cells expressing HORMAD1. In addition to the translesion synthesis (TLS) polymerase POLH, we identified a HORMAD1-driven dependency upon additional TLS polymerases, namely POLK, REV1, REV3L and REV7. Our data confirms that out-of-context somatic expression of HORMAD1 can lead to genomic instability and reveals that HORMAD1 expression induces dependencies upon replication stress tolerance pathways, such as translesion synthesis. Our data also suggest that HORMAD1 expression could be a patient selection biomarker for agents targeting replication stress.

Background The efficacy and safety of olaparib compared with placebo in the subset of patients from Japan in the phase 3 OlympiA trial (NCT02032823) are reported here and contextualized with reference to the global OlympiA population. Methods Patients with germline BRCA1 and/or BRCA2 pathogenic variants and HER2-negative, high-risk early breast cancer who had received neoadjuvant or adjuvant chemotherapy and completed local treatment were eligible. Patients were randomized 1:1 to receive olaparib or placebo for 1 year. Primary endpoint: invasive disease-free survival (IDFS). Secondary endpoints: distant disease-free survival (DDFS), overall survival (OS), and safety. Data are reported from the first pre-specified interim analysis (data cut-off [DCO] March 27, 2020) and the second, event driven, pre-specified interim analysis of OS (DCO July 12, 2021) in patients from Japan. Results 140 patients were randomized in Japan (olaparib, n = 64; placebo, n = 76). At the first pre-specified interim analysis (median follow-up: 2.9 years), hazard ratios (HRs) for adjuvant olaparib compared with placebo were 0.5 for IDFS (95% confidence interval [CI] 0.18–1.24) and 0.41 for DDFS (95% CI 0.11–1.16). At the second pre-specified interim analysis of OS, three deaths occurred in the olaparib group versus six deaths in the placebo group (HR, 0.62 [95% CI 0.13–2.36]). Findings were consistent with those for the global population. No new safety signals were observed. Conclusions While this analysis in a Japanese subset of patients was not powered to detect population-related treatment differences, efficacy and safety analysis results were consistent with the global OlympiA population, suggesting the findings from the global study are generalizable to clinical practice in Japan.

Purpose Heat-and-moisture-exchanging devices (HME) are commonly used by endurance athletes during training in sub-zero environments, but their effects on performance are unknown. We investigated the influence of HME usage on running performance at − 15 °C. Methods Twenty-three healthy adults (15 male, 8 female; age 18–53 years; $$\dot{V}{\text O}_{2peak}$$ V ˙ O 2 p e a k men 56 ± 7, women 50 ± 4 mL·kg−1·min−1) performed two treadmill exercise tests with and without a mask-style HME in a randomised, crossover design. Participants performed a 30-min submaximal warm-up (SUB), followed by a 4-min maximal, self-paced running time-trial (TT). Heart rate (HR), respiratory frequency (fR), and thoracic area skin temperature (Tsk) were monitored using a chest-strap device; muscle oxygenation (SmO2) and deoxyhaemoglobin concentration ([HHb]) were derived from near-infra-red-spectroscopy sensors on m. vastus lateralis; blood lactate was measured 2 min before and after the TT. Results HME usage reduced distance covered in the TT by 1.4%, despite similar perceived exertion, HR, fR, and lactate accumulation. The magnitude of the negative effect of the HME on performance was positively associated with body mass (r2 = 0.22). SmO2 and [HHb] were 3.1% lower and 0.35 arb. unit higher, respectively, during the TT with HME, and Tsk was 0.66 °C higher during the HME TT in men. HR (+ 2.7 beats·min−1) and Tsk (+ 0.34 °C) were higher during SUB with HME. In the male participants, SmO2 was 3.8% lower and [HHb] 0.42 arb. unit higher during SUB with HME. Conclusion Our findings suggest that HME usage impairs maximal running performance and increases the physiological demands of submaximal exercise.

Platinum derivatives are commonly used for the treatment of patients with metastatic triple-negative breast cancer (TNBC). However, resistance often develops, leading to treatment failure. This expansion cohort (part C2) of the previously reported phase 1b trial (NCT02157792) is based on the recommended phase 2 dose of the combination of the ataxia-telangiectasia and Rad3-related (ATR) inhibitor berzosertib and cisplatin observed in patients with advanced solid tumors, including TNBC. Forty-seven patients aged ≥18 years with advanced TNBC received cisplatin (75 mg/m2; day 1) and berzosertib (140 mg/m2; days 2 and 9), in 21-day cycles. Berzosertib was well tolerated, with a similar toxicity profile to that reported previously for this combination. The overall response rate (90% confidence interval) was 23.4% (13.7, 35.8). No relevant associations were observed between response and gene alterations. Further studies combining ATR inhibitors with platinum compounds may be warranted in highly selected patient populations.

Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer1,2. The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability3. Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability4–6. Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression of TRIM37. To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material—these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37-dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers. TRIM37 overexpression promotes centrosome dysfunction that drives genomic instability in breast cancer cell lines containing the recurrent 17q23 amplicon, revealing a vulnerability that can be targeted to eliminate cancer cells.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC. ispartof: NPJ BREAST CANCER vol:7 issue:1 ispartof: location:United States status: published

PARP enzymes utilise NAD+ as a co-substrate for their enzymatic activity. Inhibition of PARP1 is synthetic lethal with defects in either BRCA1 or BRCA2. In order to assess whether other genes implicated in NAD+ metabolism were synthetic lethal with BRCA1 or BRCA2 gene defects, we carried out a genetic screen, which identified a synthetic lethality between BRCA1 and genetic inhibition of either of two sirtuin (SIRT) enzymes, SIRT1 or SIRT6. This synthetic lethal interaction was replicated using small-molecule SIRT inhibitors and was associated with replication stress and increased cellular PARylation, in contrast to the decreased PARylation associated with BRCA-gene/PARP inhibitor synthetic lethality. SIRT/BRCA1 synthetic lethality was reversed by genetic ablation of either PARP1 or the histone PARylation factor-coding gene HPF1, implicating PARP1/HPF1-mediated serine ADP-ribosylation as part of the mechanistic basis of this synthetic lethal effect. These observations suggest that PARP1/HPF1-mediated serine ADP-ribosylation, when driven by SIRT inhibition, can inadvertently inhibit the growth of BRCA-gene mutant cells., Bajrami, Walker et al. investigated the synthetic lethality between BRCA gene defects and inhibition of two sirtuin genes, SIRT1 or SIRT6, which was found to be associated with replication stress and increased PARylation. The authors demonstrated that the SIRT/BRCA1 synthetic lethality was reversed by genetic ablation of PARP1 or HPF1.

Background:Childhood obesity is a global health concern. Early intervention to help parents adopt best practice for infant feeding and physical activity is critical for maintaining healthy weight. Australian governments provide universal free primary healthcare from child and family health nurses (CFHNs) to support families with children aged up to five years and to provide evidence-based advice to parents. This paper aims to examine factors influencing the child obesity prevention practices of CFHNs and to identify opportunities to support them in promoting healthy infant growth. Methods:This mixed methods study used a survey (n = 90) and semi-structured interviews (n = 20) with CFHNs working in two local health districts in Sydney, Australia. Survey data were analysed descriptively; interview transcripts were coded and analysed iteratively. Survey and interview questions examined how CFHNs addressed healthy infant feeding practices, healthy eating, active play and limiting sedentary behaviour during routine consultations; factors influencing such practices; and how CFHNs could be best supported. Results:CFHNs frequently advised parents on breastfeeding, introducing solid foods, and techniques for settling infants. They spent less time providing advice on evidence-based formula feeding practices or encouraging physical activity in young children. Although nurses frequently weighed and measured children, they did not always use growth charts to identify those at risk of becoming overweight or obese. Nurses identified several barriers to promoting healthy weight gain in infants and young children, including limited parental recognition of overweight in their children or motivation to change diet or lifestyle; socioeconomic factors (such as the cost of healthy food); and beliefs and attitudes about infant weight and the importance of breastfeeding and physical activity amongst parents and family members. Conclusions:CFHNs require further education and support for their role in promoting optimal child growth and development, especially training in behaviour change techniques to increase parents' understanding of healthy infant weight gain. Parent information resources should be accessible and address cultural diversity. Resources should highlight the health effects of childhood overweight and obesity and emphasise the benefits of breastfeeding, appropriate formula feeding, suitable first foods, responsiveness to infant feeding cues, active play and limiting screen time.

Gaseous Electron Multiplier detectors, or GEMs, show promise for use on space-based X-ray missions. Operating pressure strongly affects the gain of the detector and must be optimized for best performance. We have measured the gain characteristics of a GEM detector at various pressures below atmosphere using a mixture of Ar:CO2 with the goal of maximizing gain to push GEM capabilities to the lowest energies possible. This paper discusses our tests, results, and their implications for choosing a detector pressure. We found that at any operating pressure the detector voltage can be adjusted to achieve roughly the same maximum gain prior to the onset of electrical discharges. We also find that the gain varies substantially by spatial location across the detector, but this variation is insensitive to changes in pressure allowing it to be calibrated and corrected if necessary. The detector pressure can therefore be optimized in the interest of other performance parameters such as leak rate, window stress, power requirements, or quantum efficiency without concern for negatively affecting the gain. These results can inform the choice of operating pressure and voltage for GEMs used onboard future space missions.

The TACT trial is the largest study assessing the benefit of taxanes as part of adjuvant therapy for early breast cancer. The goal of this translational study was to clarify the predictive and prognostic value of Tau within the TACT trial. Tissue microarrays (TMA) were available from 3,610 patients. ER, PR, HER2 from the TACT trial and Tau protein expression was determined by immunohistochemistry on duplicate TMAs. Two parallel scoring systems were generated for Tau expression ('dichotomised' vs. 'combined' score). The positivity rate of Tau expression was 50 % in the trial population (n = 2,483). Tau expression correlated positively with ER (p < 0.001) and PR status (p < 0.001); but negatively with histological grade (p < 0.001) and HER2 status (p < 0.001). Analyses with either scoring systems for Tau expression demonstrated no significant interaction between Tau expression and efficacy of docetaxel. Contrary to the hypothesis that taxane benefit would be enriched in Tau negative/low patients, the only groups with a suggestion of a reduced event rate in the taxane group were the HER2-positive, Tau positive subgroups. Tau expression was seen to be a prognostic factor on univariate analysis associated with an improved DFS, independent of the treatment group (p < 0.001). It had no prognostic value in ER-negative tumours and the weak prognostic effect of Tau in ER-positive tumours (p = 0.02) diminished, when considering ER as an ordinal variable. On multivariable analyses, Tau had no prognostic value in either group. In addition, no significant interaction between Tau expression and benefit from docetaxel in patients within the PR-positive and negative subsets was seen. This is now the second large adjuvant study, and the first with quantitative analysis of ER and Tau expression, failing to show an association between Tau and taxane benefit with limited utility as a prognostic marker for Tau in ER-positive early breast cancer patients.

Item does not contain fulltext All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

Future NASA X-ray spectroscopy missions will require high throughput, high resolution grating spectrometers. Off-plane reflection gratings are capable of meeting the performance requirements needed to realize the scientific goals of these missions. We have identified a novel grating fabrication method that utilizes common lithographic and microfabrication techniques to produce the high fidelity groove profile necessary to achieve this performance. Application of this process has produced an initial pre-master that exhibits a radial (variable line spacing along the groove dimension), high density (>6000 grooves/mm), laminar profile. This pre-master has been tested for diffraction efficiency at the BESSY II synchrotron light facility and diffracts up to 55% of incident light into usable spectral orders. Furthermore, tests of spectral resolving power show that these gratings are capable of obtaining resolutions well above 1300 ($\lambda/\Delta\lambda$) with limitations due to the test apparatus, not the gratings. Obtaining these results has provided confidence that this fabrication process is capable of producing off-plane reflection gratings for the next generation of X-ray observatories., Comment: 17 pages, 10 figures, Submitted to Experimetal Astronomy

Two semi-specific microbial biosensors were constructed for the analysis of biochemical oxygen demand (BOD) in high-cellulose-content pulp and paper industry wastewaters. The biosensors were based on living cells of Bacillus subtilis and Paenibacillus sp. immobilized in an agarose gel matrix. Semi-specific microorganisms were isolated from various samples (decaying sawdust and rabbit manure) and were chosen based on their ability to assimilate cellulose.The biosensors were calibrated with the Organization for Economic Cooperation and Development synthetic wastewater, and measurements with different wastewaters were conducted.The response time of biosensors using the steady-state method was 20-25 min, and the service life of immobilized microorganisms was 96 days. Detection limit was 5 mg/l of BOD(7) while linear ranges extended up to 55 and 50 mg/l of the BOD(7) for B. subtilis- and Paenibacillus sp.-based biosensors, respectively. Repeatability and reproducibility of both biosensors were within the limits set by APHA-less than 15.4%. In comparison, both biosensors overestimated the BOD(7) values in paper mill wastewaters and underestimated the BOD(7) in aspen pulp mill wastewater.The semi-specific biosensors are suitable for the estimation of organic pollution derived from cellulose, while the detection of pollution derived from tannins and lignins was minor. Better results in terms of accuracy and repeatability were gained with Paenibacillus sp. biosensor.

The triple-negative breast cancer (TNBC) phenotype, defined as the lack of estrogen and progesterone hormone receptors and the HER2 receptor, represents approximately 15% to 20% of all breast cancer cases. Challenges faced in management of these patients arise from the heterogeneity of TNBC and the absence of well-defined molecular targets. Subgroups derive significant benefit from cytotoxics however, patients with TNBC have higher rates of distant recurrence and a poorer prognosis than women with other breast cancer subtypes overall. Currently, cytotoxic chemotherapy is the only systemic treatment option at all stages of disease, and rational drug selection based on tumor biology remains an aspiration. In the context of relapse, the most efficacious regimens remain undefined and the typical clinical picture is one of rapid disease progression and little durable benefit to therapy. This article reviews current approaches in metastatic TNBC and considers novel therapies in development that may improve the outlook for those with this disease.

The use of neoadjuvant systemic therapy (NST) for the treatment of primary breast cancer has constantly increased, especially in trials of new therapeutic regimens. In the 1980 s, NST was shown to substantially improve breast-conserving surgery rates and was first typically used for patients with inoperable locally advanced or inflammatory breast cancer. Investigators have since also used NST as an in vivo test for chemosensitivity by assessing pathologic complete response. Today, by using pathologic response and other biomarkers as intermediate end points, results from trials of new regimens and therapies that use NST are aimed to precede and anticipate the results from larger adjuvant trials. In 2003, a panel of representatives from various breast cancer clinical research groups was first convened in Biedenkopf to formulate recommendations on the use of NST. The obtained consensus was updated in two subsequent meetings in 2004 and 2006. The most recent conference on recommendations on the use of NST took place in 2010 and forms the basis of this report.

Studies comparing the prognosis after contralateral breast cancer (CBC) with that after unilateral breast cancer (UBC) shows conflicting results. We assessed the risk of breast cancer-specific death for women with metachronous CBC compared to those with a UBC in 8,478 women with invasive primary breast cancer registered in the Guy's and St. Thomas' Breast Cancer Tissue and Data Bank. Risk factors associated with breast cancer-specific death for women with CBC were estimated using Cox proportional hazards modelling. Prognoses after UBC and CBC were compared, with survival time for women with CBC calculated: (i) from CBC, (ii) from the initial cancer with CBC as a time-dependent covariate. Women diagnosed with CBC within 5 years after the initial primary breast cancer had a worse prognosis than those with CBC after 5 years and those with UBC. Women with CBC who had positive lymph nodes at the initial breast cancer diagnosis were at an increased risk of dying from breast cancer compared to those without [HR 2.5 (95% CI 1.5-4.0)]. For all stages of the initial breast cancer, a worse prognosis was observed after CBC. CBC increased the hazard originating from the initial cancer at any follow-up time, but the highest hazards were associated with a short interval to CBC. Metachronous CBC adds to the risk of dying from breast cancer. The risk increases substantially when it occurs shortly after the initial cancer, indicating a CBC in some instances may be an indicator of active distant disease. The occurrence of CBC implies a new surveillance and therapeutic situation.

The purpose of this study is to measure the impact of a multidisciplinary one-stop follow-up clinic (MDOSC) on breast and ovarian surveillance, risk reducing surgery and enrolment in clinical trials in BRCA1/2 carriers. All BRCA1/2 carriers in our region were invited and chose which specialists to see in our MDOSC offering best practice using clinical protocols based on national guidelines and published data. Uptake was evaluated over 24 months recording numbers of individuals undergoing breast and ovarian surveillance, risk reducing surgery, newly diagnosed cancers, their method of detection and participation in clinical trials. 172 (60%) of invited BRCA1/2 carriers chose to attend the MDOSC. Breast surveillance was initiated in 88% and screening frequency altered in 14% of women to comply with national guidelines. Risk reducing salpingo-oophorectomy was chosen by 47% of women and an additional 39% were considering it. The rate of failure to remove fallopian tubes fell from 15 to 3% of procedures (P < 0.01) and peritoneal washings and serial sectioning of tubes and ovaries rose from 25% and 14% before, to 67% (P < 0.001) and 63% (P < 0.001) procedures, respectively, after initiation of our MDOSC. 24% of women considered and 18% decided to undergo risk reducing mastectomy during the follow-up period. Participation in clinical trials increased significantly from 51 to 229 enrolments (P < 0.001). Our novel MDOSC designed to devise an individually tailored cancer risk management strategy had a high uptake amongst our BRCA1/2 carriers. Attendance resulted in improved breast and ovarian cancer risk management.

To examine the impact of enforcement of age-restricted tobacco sales on adolescent tobacco purchasing and smoking, we compared the Central Coast intervention area to the rest of New South Wales (NSW) and Australia. We collected data on students in school years 7-12 from triennial health surveys at baseline in 1993 through 2002. Attempts by minors to purchase tobacco in the intervention area declined by 73.6 per cent between 1993 and 2002. Between 1993 and 1996 the prevalence of smoking declined in the Central Coast intervention area, while remaining unchanged in NSW as a whole and nationally (P