Time-resolved optical absorption microspectroscopy of magnetic field sensitive flavin photochemistry

The photochemical reactions of blue-light receptor proteins have received much attention due to their very important biological functions. In addition, there is also growing evidence that the one particular class of such proteins, the cryptochromes, may be associated with not only a biological photo-response but also a magneto-response, which may be responsible for the mechanism by which many animals can respond to the weak geomagnetic field. Therefore, there is an important scientific question over whether it is possible to directly observe such photochemical processes, and indeed the effects of weak magnetic fields thereon, taking place both in purified protein samples in vitro and in actual biochemical cells and tissues. For the former samples, the key lies in being able to make sensitive spectroscopic measurements on very small volumes of samples at potentially low protein concentrations, while the latter requires, in addition, spatially resolved measurements on length scales smaller than typical cellular components, i.e., sub-micron resolution. In this work, we discuss a two- and three-color confocal pump-probe microscopic approach to this question which satisfies these requirements and is thus useful for experimental measurements in both cases

The British Army in Transition: from army 2020 to the Strike Brigades and the logistics of future operations

The financial crisis of 2008 and the economic recession that followed forced the UK Government to adopt measures to reduce public spending in order to deal with a growing budgetary deficit and the UK's spiralling sovereign debt. Like most other departments, the Ministry of Defence (MOD) had to play its part, as well as tackling a massive funding gap in its equipment plan. While 2010's Strategic Defence and Security Review (SDSR)[i] and the National Security Strategy (NSS)[ii] have been criticised as lacking any real strategic intent[iii], they did at least attempt to tackle the MOD's budgetary problems. It also set in motion an ongoing programme of structural change, for both the MOD and the UK Armed Forces, that has continued after the publication of SDSR 2015[iv] and meant that the MOD has faced a difficult period – having to juggle the need to conduct major transformation, change the way it acquires defence capability, and restructure the armed forces while continuing to conduct operations in both Iraq and Afghanistan. This paper aims to examine the impact of both SDSRs on the British Army, and takes a broadly chronological approach in doing so. It analyses the new 'Strike Brigade' concept and what that might mean for defence acquisition and the logistic support to future operations, while highlighting the questions still surrounding the outcome of the latest review

Exercise attenuates cardiotoxicity of anthracycline chemotherapy measured by global longitudinal strain [Letter]

[Extract] Anthracycline-based chemotherapy (AC) is a common treatment for patients with breast cancer and has been associated with a dramatic improvement in breast cancer survivorship. Among patients with early-stage breast cancer, cardiovascular diseases represent the most common cause of mortality, and there is a growing emphasis on strategies for minimizing the toxic effects of breast cancer treatments on the cardiovascular system (1)

Exercise attenuates cardiotoxicity of anthracycline chemotherapy measured by global longitudinal strain [Letter]

[Extract] Anthracycline-based chemotherapy (AC) is a common treatment for patients with breast cancer and has been associated with a dramatic improvement in breast cancer survivorship. Among patients with early-stage breast cancer, cardiovascular diseases represent the most common cause of mortality, and there is a growing emphasis on strategies for minimizing the toxic effects of breast cancer treatments on the cardiovascular system (1)

A Camera-Based Method for Collecting Rapid Vegetation Data to Support Remote-Sensing Studies of Shrubland Biodiversity

The decline in biodiversity in Mediterranean-type ecosystems (MTEs) and other shrublands underscores the importance of understanding the trends in species loss through consistent vegetation mapping over broad spatial and temporal ranges, which is increasingly accomplished with optical remote sensing (imaging spectroscopy). Airborne missions planned by the National Aeronautics and Space Administration (NASA) and other groups (e.g., US National Ecological Observatory Network, NEON) are essential for improving high-quality maps of vegetation and plant species. These surveys require robust and efficient ground calibration/validation data; however, barriers to ground-data collection exist, such as steep terrain, which is a common feature of Mediterranean-type ecosystems. We developed and tested a method for rapidly collecting ground-truth data for shrubland plant communities across steep topographic gradients in southern California. Our method utilizes semi-aerial photos taken with a high-resolution digital camera mounted on a telescoping pole to capture groundcover, and a point-intercept image-classification program (Photogrid) that allows efficient sub-sampling of field images to derive vegetation percent-cover estimates while reducing human bias. Here, we assessed the quality of data collection using the image-based method compared to a traditional point-intercept ground survey and performed time trials to compare the efficiency of various survey efforts. The results showed no significant difference in estimates of percent cover and Simpson&rsquo;s diversity derived from the point-intercept and those derived using the image-based method; however, there was lower correspondence in estimates of species richness and evenness. The image-based method was overall more efficient than the point-intercept surveys, reducing the total survey time by 13 to 46 min per plot depending on sampling effort. The difference in survey time between the two methods became increasingly greater when the vegetation height was above 1 m. Due to the high correspondence between estimates of species percent cover derived from the image-based compared to the point-intercept method, we recommend this type of survey for the verification of remote-sensing datasets featuring percent cover of individual species or closely related plant groups, for use in classifying UAS imagery, and especially for use in MTEs that have steep, rugged terrain and other situations such as tall, dense-growing shrubs where traditional field methods are dangerous or burdensome. </dl

Australian clinicians and chemoprevention for women at high familial risk for breast cancer

<p>Abstract</p> <p>Objectives</p> <p>Effective chemoprevention strategies exist for women at high risk for breast cancer, yet uptake is low. Physician recommendation is an important determinant of uptake, but little is known about clinicians' attitudes to chemoprevention.</p> <p>Methods</p> <p>Focus groups were conducted with clinicians at five Family Cancer Centers in three Australian states. Discussions were recorded, transcribed and analyzed thematically.</p> <p>Results</p> <p>Twenty three clinicians, including genetic counselors, clinical geneticists, medical oncologists, breast surgeons and gynaecologic oncologists, participated in six focus groups in 2007. The identified barriers to the discussion of the use of tamoxifen and raloxifene for chemoprevention pertained to issues of evidence (evidence for efficacy not strong enough, side-effects outweigh benefits, oophorectomy superior for mutation carriers), practice (drugs not approved for chemoprevention by regulatory authorities and not government subsidized, chemoprevention not endorsed in national guidelines and not many women ask about it), and perception (clinicians not knowledgeable about chemoprevention and women thought to be opposed to hormonal treatments).</p> <p>Conclusion</p> <p>The study demonstrated limited enthusiasm for discussing breast cancer chemoprevention as a management option for women at high familial risk. Several options for increasing the likelihood of clinicians discussing chemoprevention were identified; maintaining up to date national guidelines on management of these women and education of clinicians about the drugs themselves, the legality of "off-label" prescribing, and the actual costs of chemopreventive medications.</p

Nipple aspiration and ductal lavage in women with a germline BRCA1 or BRCA2 mutation

INTRODUCTION: The aim of this study was to collect serial samples of nipple aspirate (NA) and ductal lavage (DL) fluid from women with germline BRCA1/2 mutations in order to create a biorepository for use in identifying biomarkers of breast cancer risk. METHODS: Between March 2003 and February 2005, 52 women with germline BRCA1 or BRCA2 mutations (median age 43 years, range 27 to 65 years) were scheduled for six-monthly NA, DL and venesection. DL was attempted for all NA fluid-yielding (FY) and any non-FY ducts that could be located at each visit. RESULTS: Twenty-seven (52%) women were postmenopausal, predominantly (19/27) from risk reducing bilateral salpingo-oophorectomy (BSO). FY ducts were identified in 60% of all women, 76% of premenopausal women versus 44% of postmenopausal (P = 0.026). Eighty-five percent of women had successful DL. Success was most likely in women with FY ducts (FY 94% versus non-FY 71% (P = 0.049). DL samples were more likely to be cellular if collected from FY ducts (FY 68% versus non-FY 43%; P = 0.037). Total cell counts were associated with FY status (FY median cell count 30,996, range 0 to >1,000,000 versus non-FY median cell count 0, range 0 to 173,577; P = 0.002). Four women (8%) had ducts with severe atypia with or without additional ducts with mild epithelial atypia; seven others had ducts with mild atypia alone (11/52 (21%) in total). Median total cell count was greater from ducts with atypia (105,870, range 1920 to >1,000,000) than those with no atypia (174, 0 to >1,000,000; P ≤ 0.001). CONCLUSION: It is feasible to collect serial NA and DL samples from women at high genetic risk of breast cancer, and we are creating a unique, prospective collection of ductal samples that have the potential to be used for discovery of biomarkers of breast cancer risk and evaluate the ongoing effects of risk reducing BSO. DL cellular atypia was not predictive of a current breast cancer and longer follow up is needed to determine whether atypia is an additional marker of future breast cancer risk in this population already at high genetic risk of breast cancer

Therapeutic options for mucinous ovarian carcinoma

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition

A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome

Published online 26 April 2023Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.Romy Walker ... Nicola Poplawski ... et al. and for the Family Cancer Clinics of Australi