Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy.

Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged for its regulatory roles in immune cell function, cell adhesion, and vascular development. This study presents evidence indicating that Syk expression in high-grade serous ovarian cancer and triple-negative breast cancers promotes DNA double-strand break resection, homologous recombination (HR), and subsequent therapeutic resistance. Our investigations reveal that Syk is activated by ATM following DNA damage and is recruited to DNA double-strand breaks by NBS1. Once localized to the break site, Syk phosphorylates CtIP, a pivotal mediator of resection and HR, at Thr-847 to promote repair activity, particularly in Syk-expressing cancer cells. Inhibition of Syk or its genetic deletion impedes CtIP Thr-847 phosphorylation and overcomes the resistant phenotype. Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.

Racial disparities in pain management: Historical maleficence and solutions for equity.

ABSTRACT: Medical journals from the 1800s described differences in disease susceptibility, skin thickness, and pain tolerance among races. These misconceptions about biologic differences, the historical exploitation of minorities in research, and implicit biases among healthcare workers have all affected patient care. Discrepancies still exist in pain assessment and management for minority patients compared with their White counterparts and lead to poor health outcomes. By implementing specific changes in policy and practice, including standardization, implicit bias training, and building a diverse workforce, clinicians can begin to provide care that more equitably manages pain for all patients, regardless of race.

Syk-dependent alternative homologous recombination activation promotes cancer resistance to DNA targeted therapy.

Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase known to regulate immune cell function, cell adhesion, and vascular development. Here, we report that Syk can be expressed in high grade serous ovarian cancer and triple negative breast cancers and promotes DNA double strand break resection, homologous recombination (HR) and therapeutic resistance. We found that Syk is activated by ATM following DNA damage and is recruited to DNA double strand breaks by NBS1. Once at the break site, Syk phosphorylates CtIP, a key mediator of resection and HR, at Thr-847 to promote repair activity, specifically in Syk expressing cancer cells. Syk inhibition or genetic deletion abolished CtIP Thr-847 phosphorylation and overcame the resistant phenotype. Collectively, our findings suggest that Syk drives therapeutic resistance by promoting DNA resection and HR through a novel ATM-Syk-CtIP pathway, and that Syk is a new tumor-specific target to sensitize Syk-expressing tumors to PARPi and other DNA targeted therapy.

COVID-19 Awareness and Preparedness of Minnesota and Wisconsin Dairy Farms.

Dairy farms that had participated in previous and ongoing projects with the National Farm Medicine Center (NFMC), Migrant Clinicians Network (MCN), and Upper Midwest Agricultural Safety and Health Center (UMASH) were asked to participate in a 17-question survey by phone or email to investigate biosecurity principles on Minnesota and Wisconsin dairy farms in response to COVID-19 and the effects of the pandemic on the dairy industry. Three additional farms were recruited via a press release published in agricultural newsletters. Of 76 farms contacted, 37 chose to participate in this study from June to July 2020. In response to the COVID-19 pandemic, dairies have implemented or increased biosecurity measures and COVID-19 precautions. Dairies reported adequate personal protective equipment for their workers, though face masks were not required on most dairies (n = 32, 86%). Producers were concerned about the safety of their families, maintaining a healthy workforce, and keeping their farms profitable. Access to healthcare was not perceived to be an issue for their workers. One-quarter of dairies reported COVID-19 infections on their farms. Even though the majority had an isolation protocol in place if someone on the farm were to become ill, less than half of respondents felt their farm was protected against COVID-19. Two-thirds of producers have not had to decrease production, and a majority of operations have not furloughed or terminated employees due to COVID-19. Our data suggest that dairy farms in Minnesota and Wisconsin have implemented biosecurity and safety measures in response to COVID-19. These measures can be improved. Farms would benefit from additional guidance and education on implementation of personal protective measures and disease prevention strategies to keep workers employed and safe.

Cells deficient for Krüppel-like factor 4 exhibit mitochondrial dysfunction and impaired mitophagy.

Krüppel-like factor 4 (Human Protein: KLF4; Human Gene: Klf4; Murine Protein: KLF4; Murine Gene: Klf4) is a zinc finger-containing transcription factor with diverse regulatory functions. Mouse embryonic fibroblasts (MEFs) lacking Klf4 exhibit genomic instability, increased reactive oxygen species (ROS), and decreased autophagy. Elevated ROS is linked to impairments in mitochondrial damage recovery responses and is often tied to disruption in mitochondrial-targeted autophagy known as mitophagy. In this study, we sought to identify a mechanistic connection between KLF4 and mitophagy. Using flow cytometry, we found that Klf4-null MEFs have diminished ability to recover mitochondrial health and regulate ROS levels after mitochondrial damage. Confocal microscopy indicated decreased localization of autophagy protein LC3 to mitochondria following mitochondrial damage in Klf4-null cells, suggesting decreased mitophagy. Western blotting and RT-PCR revealed decreased mRNA and protein expression of the mitophagy-associated protein Bnip3 and antioxidant protein GSTα4 in Klf4-null cells, providing a rationale for their impaired mitophagy and ROS accumulation. Inducing Bnip3 expression in these cells recovered mitophagy but did not decrease ROS accumulation. Our findings suggest that in Klf4-null cells, decreased Bnip3 expression impairs mitophagy and is associated with increased mitochondrial ROS production after mitochondrial damage, providing a rationale for their genomic instability and supports a tumor suppressive role for KLF4 in certain tumors as previously observed.

Sex and cardiovascular disease status differences in attitudes and willingness to participate in clinical research studies/clinical trials.

BACKGROUND: While women are under-represented in research on cardiovascular disease (CVD), little is known about the attitudes of men and women with CVD regarding participation in clinical research studies/clinical trials. METHODS: Patients with CVD (and/or risk factors) and patients with other chronic conditions from Iowa were recruited from a commercial panel. An on-line survey assessed willingness to participate (WTP) and other attitudes towards aspects of clinical research studies. RESULTS: Based on 504 respondents, there were no differences in WTP in patients with CVD compared to patients with other chronic diseases. Across all respondents, men had 14% lower WTP (relative risk (RR) for men, 0.86, 95% CI, 0.72-1.02). Among patients with CVD, there was no significant difference in WTP between women (RR for women = 1) and men (RR for men, 0.96, 95% CI, 0.82-1.14). There were no significant differences based on sex or CVD status for attitudes on randomization, blinding, side effects, conflict of interest, experimental treatments or willingness to talk to one's physician. Women had more favorable attitudes about participants being treated like "guinea pigs" (RR for men, 0.84, 95% CI, 0.73-0.98) and clinical trials being associated with terminally ill patients (RR for men, 0.93, 95% CI, 0.86-1.00). CONCLUSIONS: The findings reported here suggest that the observed lower levels of participation by women are due to factors other than a lower WTP or to women having more negative attitudes towards aspects of study participation. Patients with CVD have similar attitudes and WTP as patients with other chronic conditions.

Dosimetric aspects of breast radiotherapy with three-dimensional and intensity-modulated radiotherapy helical tomotherapy planning modules.

In this work, we investigated the dosimetric differences between the intensity-modulated radiotherapy (IMRT) plans and the three-dimensional (3D) helical plans based on the TomoTherapy system. A total of 15 patients with supine setup were randomly selected from the data base. For patients with lumpectomy planning target volume (PTV), regional lymph nodes were also included as part of the target. For dose sparing, the significant differences between the helical IMRT and helical 3D were only found in the heart and contralateral breast. For the dose to the heart, helical IMRT reduced the maximum point dose by 6.98Gy compared to the helical 3D plan (p = 0.01). For contralateral breast, the helical IMRT plans significantly reduced the maximum point dose by 5.6Gy compared to the helical 3D plan. However, compared to the helical 3D plan, the helical IMRT plan increased the volume for lower dose (13.08% increase in V5Gy, p = 0.01). In general, there are no significant differences in dose sparing between helical IMRT and helical 3D plans.

Resiliency scoring for business continuity plans.

Through this paper readers will learn of a scoring methodology, referred to as resiliency scoring, which enables the evaluation of business continuity plans based upon analysis of their alignment with a predefined set of criteria that can be customised and are adaptable to the needs of any organisation. This patent pending tool has been successful in driving engagement and is a powerful resource to improve reporting capabilities, identify risks and gauge organisational resilience. The role of business continuity professionals is to aid their organisations in planning and preparedness activities aimed at mitigating the impacts of potential disruptions and ensuring critical business functions can continue in the event of unforeseen circumstances. This may seem like a daunting task for what can typically be a small team of individuals. For this reason, it is important to be able to leverage industry standards, documented best practices and effective tools to streamline and support your continuity programme. The resiliency scoring methodology developed and implemented at Target has proven to be a valuable tool in taking the organisation's continuity programme to the next level. This paper will detail how the tool was developed and provide guidance on how it can be customised to fit your organisation's unique needs.

Hearing Health in College Instrumental Musicians and Prevention of Hearing Loss.

OBJECTIVE: College musicians exhibit greater declines in hearing than the general population and are at particular risk because they rehearse and perform daily in loud environments. Also, they engage in use of personal listening devices which increases the amount of "exposure" time. Despite increased risk, many do not use hearing protection devices (HPD). The purpose of this study was to (1) to identify the present level of education about hearing health, (2) identify the perceived advantages and disadvantages of using HPD, and (3) evaluate results among different musical instrument groups. METHODS: A mixed-methods group design was used including both quantitative and qualitative instruments. SPSS was used to generate descriptive statistics, and non-parametric statistical analysis was performed on quantitative data. NVivo software was used to evaluate qualitative responses. RESULTS: Of the 90 college instrumental music students who participated, 12% reported a history of hearing loss, and over one-third reported tinnitus. Seventy-seven percent of participants had never received any training about hearing health and only a small percentage of students used HPD. The most cited reason for lack of protection use was its negative impact on sound quality. However, group differences were noted between brass, woodwind, and percussion musicians in terms of HPD uptake. CONCLUSION: Improving the type of information disseminated to college musicians may reduce the risk of ear-related deficits. Noise dosage information, HPD information, and prevention education grounded in theories like the Health Belief Model may increase awareness and promote greater use of HPDs in this population.

Acute Toxicity From Breast Cancer Radiation Using Helical Tomotherapy With a Simultaneous Integrated Boost.

PURPOSE: To evaluate 2 simultaneous integrated boost treatment planning techniques using helical tomotherapy for breast conserving therapy with regard to acute skin toxicity and dosimetry. METHODS: Thirty-two patients were studied. The original approach was for 16 patients and incorporated a directional block of the ipsilateral lung and breast. An additional 16 patients were planned for using a modified approach that incorporates a full block of the ipsilateral lung exclusive of 4 cm around the breast. Dose-volume histograms of targets and critical structures were evaluated. Skin toxicity monitoring was performed throughout treatment and follow-up using the Common Terminology Criteria for Adverse Events. RESULTS: Treatment was well tolerated with patients receiving a median dose of 59.36 Gy. Of the 16 patients in both groups, 8 had grade 2 erythema immediately after radiation. On 3-week follow-up, 10 and 7 patients in the original and modified groups showed grade 1 erythema. On 3- and 6-month follow-up, both groups had minimal erythema, with all patients having either grade 0 or 1 symptoms. No grade 2 or 3 toxicities were reported. Mean treatment time was 7.5 and 10.4 minutes using the original and modified methods. Adequate dose coverage was achieved using both methods (V95 = 99.5% and 98%). Mean dose to the heart was 10.5 and 1.8 Gy, respectively (P < .01). For right-sided tumors, the original and modified plans yielded a mean of 8.8 and 1.1 Gy (P < .01) versus 11.7 and 2.4 Gy for left-sided tumors (P < .01). The mean dose to the ipsilateral lung was also significantly lower in the modified plans (11.8 vs. 5.0 Gy, P < .01). CONCLUSIONS: Tomotherapy is capable of delivering homogeneous treatment plans to the whole breast and lumpectomy cavity using simultaneous integrated boost treatment. Using the treatment methods described herein, extremely low doses to critical structures can be achieved without compromising acute skin toxicity.