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Abstract: COVID-19 is caused by the SARS-CoV-2 virus, which has afflicted more than 245.37 million individuals worldwide and resulted in more than 4.9 million deaths as of today, with a mortality rate of 2.1%. Diabetes mellitus (DM) and its secondary complications are the major serious global health concerns today due to its growth rate, and it is the fastest-growing non-communicable disease. According to International Diabetes Federation (IDF) data, one out of 11 adults is diabetic, and the projection says that the figure will reach 642 million by 2040 globally. The occurrence of DM and its secondary complications is also associated with the severity of COVID-19 and high mortality. People with DM have a weakened immune system owing to innate immunity defects affecting phagocytosis, neutrophil chemotaxis, and cellmediated immunity; however, the high prevalence of diabetes in serious cases of COVID-19 may reflect the higher prevalence of type 2 DM (T2DM) in older people. Moreover, DM is linked to cardiovascular illness in older people, which could underlie the correlation between COVID-19 and fatal outcomes. SARS-CoV-2 infects via the angiotensin-converting enzyme 2 (ACE2), which is found in pancreatic islets, and infection with SARS-CoV-1 has been linked to hyperglycemia in individuals who do not have DM. And hence diabetic patients need to take more precautions and maintain their blood glucose levels. Many pieces of research say that COVID-19 and DM, especially its secondary complications are interlinked. But it also needs more elaborative evidence on whether the anti-diabetic drugs can manage only blood glucose or SARS-CoV-2.

The research aims at the impact of strategic capabilities as an independent variable through its dimensions (technical knowledge to build value, the ability to generate and own resources, and the technology used) on the sustainable competitive advantage as a dependent variable and its dimensions (Cost, quality, delivery, flexibility) The research topics are among the current issues aimed at helping companies discover and build strategic capabilities that support the researched company in a confrontation between competing companies and the ability of the studied company to stabilize and ensure success, excellence and creativity. The researchers used the questionnaire as the primary tool for collecting Data related to the selection of a random sample of (95) respondents to analyze and display the responses of the sample members and their perceptions of the study variables and their sub-dimensions and to test the study hypotheses using descriptive and inferential statistical methods, as well as the use of field observations and personal interviews as aids in data collection. The researchers relied on statistical programs (16. SPSS V.25, Excel V) in processing and analyzing data by using the most appropriate statistical methods. The researchers reached a set of results, the most important of which is the existence of a relationship and the effect of the correlation between the independent variable, strategic capabilities and its dimensions, and the dependent variable, the sustainable competitive advantage and its dimensions. This means that sustainable competitive advantages derive the ingredients for achieving them from the components of the services provided by the researched company. Whenever the research sample companies possess the technical knowledge to build value in the presentation in delivering products and services to customers, whenever they can achieve sustainable competitive advantages within their work environment.

Objective Patients with hormone receptor positive (HR+), HER2- metastatic breast cancer frequently require radiation therapy (RT) in addition to systemic therapy for disease control and symptom management. CDK 4/6 inhibitors are increasingly used in the care of hormone positive breast cancers. Stereotactic body radiotherapy (SBRT), a form of very focused high dose radiation, is also increasingly used in the care of metastatic breast cancer. Limited data have reported on the safety of palliative RT with CDK4/6 inhibitors, with some reports demonstrating synergistic effects with potential for increased toxicity. The objective of our study is to assess toxicity among patients who received SBRT, stereotactic radiosurgery (SRS), or other high dose RT along with CDK 4/6 inhibitors for treatment of metastatic breast cancer. Methods Women with metastatic breast cancer who received SBRT, SRS, or other higher dose RT with CDK 4/6 inhibitors at any point in their treatment between 2013 and 2021 were retrospectively identified. Timing of radiation therapy, either before, during, or after CDK 4/6 inhibitor use was assessed, as well as the interval between the two treatments. Treatment sites for radiotherapy included lung/chest, spine, and brain metastases. Physician assessed adverse events were obtained through clinical follow up and graded using CTCAE v5. Local control and OS were reported. Results Twenty patients met study inclusion criteria. Patients received radiation therapy and CDK 4/6 inhibitors concurrently (within 7 days) [n=7, 35%], within 30 days (RT pre-CDK 4/6 inhibitor use) [n=3, 15%], and greater than 30 days (RT pre-CDK 4/6 inhibitor use [n=6, 30%] and RT post-CDK 4/6 inhibitor use [n=4, 20%]). Radiation treatment sites were spine [n=10, 55%], brain [n=6, 30%], and lung/chest wall [n=3, 15%]. Radiation doses were as follows: 60 Gy in 5 fractions [n=1, 5%], 50 Gy in 5 fractions [n=2, 10%], 55 Gy in 20 fractions (chest wall recurrence) [n=1, 5%], 35 Gy in 15 fractions [n=1, 5%], 30 Gy in 10 fractions [n=6, 30%], 30 Gy in 3 fractions [n= 4, 20%], 24 Gy in 1 fraction [n=3, 15%], 20 Gy in 5 fractions [n=2, 10%]. Palbociclib was used in 85% of patients [n=17] and abemaciclib in 15% [n=3]. Median follow up for surviving patients was 4.7 years [IQR: 2.5-6.8 years]. Local control was achieved in 85% of patients [n=17]. Median OS was 2.7 years [IQR: 0.1-6.8 years]. Grade 2 toxicity [n=9, 45%] and grade 3 toxicity [n=3, 15%] was reported across all three treatment areas, with grade 2 or 3 fatigue [n=7, 35%] being the most frequently reported toxicity. In the spine treatment group, 1 patient who had CDK 4/6 inhibitor use within 30 days of radiotherapy experienced a grade 3 vertebral compression fracture as well as grade 3 fatigue. In the lung/chest wall treatment group, the patient treated to 55 Gy in 20 fractions to the chest wall with concurrent use had grade 3 skin/wound toxicity requiring prolonged wound care before healing. In the intra-cranial SRS group, grade 3 fatigue was reported in 1 patient with concurrent use. Conclusion The use of CDK 4/6 inhibitors concurrently with or within 30 days of radiation therapy was generally well tolerated with limited grade 3 toxicity. Two of three reports of grade 3 toxicity occurred with concurrent treatment. Due to the potential radiosensitizing properties of CDK 4/6 inhibitors, it may be prudent to hold combined treatment when clinically feasible. Further study is needed to validate these results. Citation Format: Kiran Chauhan, Roman O. Kowalchuk, Allison E. Garda, Dean A. Shumway, Mark R. Waddle, Robert Mutter, Kimberly Corbin. Safety of stereotactic body radiation therapy, stereotactic radiosurgery, and other radiation therapy with use of CDK 4/6 inhibitors for hormone receptor positive (HR+), HER2- metastatic breast cancer: a retrospective cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-05.

The study aims to prove the controllability of mild solution for semilinar fractional integerodifferential equations with nonlocal conditions in banach spaces. Fractional calculus, compact semigroups and fixed point theorem, are concepts consulted to obtain results this work.

تناولت الدراسة تصنيف استعمالات الارض السكنية في مدينة الهندية باستخدام نظم المعلومات الجغرافية، لما له من اهمية في توضيح الحيز المكاني الذي يحتله هذا الاستعمال في منطقة الدراسة ويعكس لنا صورة التوزيع المكاني للوحدات السكنية ومعرفة اي الاحياء السكنية ذات كثافة عالية او متوسطة الكثافة او منخفضة ونمط بناء هذه الوحدات ودرجة التجاور او التلاصق ومساحة القطعة السكنية وكثافة ونسبة اشغال الوحدة السكنية، اعتمادا على برنامج (ARC GIS10.8) في التمثيل والتصنيف الكارتوكرافي. وقد توصلت الدراسة الى جملة من الاستنتاجات والتوصيات منها ان معظم الاحياء السكنية في منطقة الدراسة ذات كثافة سكنية منخفضة بسبب وجود مساحات واسعة غير مستثمرة كونها احياء حديثة وبعضها كانت اراضي زراعية وتم استخدامها كأحياء سكنية اما المحلات السكنية التي سجلت فيها اعلى نسب الكثافة السكنية العامة فأنها تقع ضمن المنطقة التجارية المركزية قديمة النشأة , ومعظم تلك المحلات السكنية جاءت باقل مساحة للقطع السكنية حيث انها لا تزيد عن (100م2) اما الاحياء السكنية فمعظمها تتراوح (200 – 300م2) باستثناء حي المثنى حيث بلغت مساحة القطع السكنية (600م2) , وان استخدام معطيات الاستشعار عن بعد ونظم المعلومات الجغرافية لها اهمية في اختصار الوقت والجهد والكلفة التي كانت تتطلبه عملية رسم الخرائط بالطرائق التقليدية وامكانية تحديثها بسهولة إضافة الى تشجيع استخدام نظم المعلومات الجغرافية في جميع دوائر الدولة.

Background: Sarcopenia, characterized by the loss of muscle mass, has emerged as a negative prognostic factor in cancer patients. It has been associated with poorer outcomes and increased treatment-related morbidity. Post-mastectomy breast radiation therapy (RT) increases the likelihood of reconstructive complication, with up to 20% of reconstructed women requiring implant removal. The factors that lead to these complications are poorly understood and likely multifaceted. We investigated the relationship between pre-radiation therapy sarcopenia and post-mastectomy reconstruction outcomes. Methods: Chart review was performed to determine demographic, medical, and treatment variables, including reconstruction complication events and failures in breasts treated with mastectomy, immediate reconstruction, and RT. Reconstruction failure was defined as tissue expander or implant removal, resulting in no final reconstruction or autologous reconstruction only. Reconstruction complications included surgical site infection, late infection (1 year post-RT), seroma development, flap necrosis, nipple necrosis, wound dehiscence, capsular contracture, hematoma, extrusion, leak, venous congestion, and unplanned reoperation. An axial slice at the L2 or L3 vertebral body from the radiation therapy planning CT scan was analyzed for skeletal muscle area using a previously validated algorithm, with manual review and adjustment as indicated. Sarcopenia was defined by skeletal muscle index (SMI, skeletal muscle area in cm2 divided by patient’s height squared) below 34.4 cm2/m2. Chi-square, Kaplan Meier, and univariate Cox regression tests were used for analysis. Results: Ninety-nine women with breast cancer who underwent mastectomy, reconstruction, and RT were included in this study. All women had immediate reconstruction: 93 women had tissue expander placement while six women had permanent implant placement. Mean age was 47.5 years (SD 10.6) at diagnosis and median BMI was 24.8. Seventy-six percent were non-smokers, 24% were former smokers, and only 16 (16.2%) and 3 (3.0%) had hypertension or diabetes, respectively. Median follow-up was 2.7 years. Median SMI was 38 cm2/m2 and 18 (18%) met criteria for sarcopenia (SMI < 34.4 cm2/m2). Mastectomy was bilateral in 79 women, skin-sparing in 61, and nipple sparing in 31. Bilateral mastectomy was less frequent amongst women with sarcopenia (61%) compared to 84% of those without sarcopenia (p=0.03). After RT, twenty-three women required unplanned reoperation. Within these 23 women, there were 45 total complications. Complications included surgical site infection (n=18), capsular contracture (n=12), seroma (n=4), wound dehiscence (n=3), and others (n=8). However, only 8 women had reconstructive failure and none were sarcopenic at the time of the RT planning scan. Any complication or failure after RT occurred in similar proportions of patients with and without sarcopenia: 38% and 30%, respectively. Kaplan-Meier curves and univariate Cox regression models showed no significant difference in time to failure (p = 0.380) or time to any event (complication or failure) (p=0.53), between sarcopenic and non-sarcopenic patients. Conclusion: Sarcopenia, using SMI < 34.4 cm2/m2 on pre-radiotherapy planning scans, was not associated with an increased risk of post-radiotherapy reconstructive complication or failure in this selected cohort of non-smokers. Few women had sarcopenia at the time of operation, and results should be validated in a larger series. Citation Format: Yasamin Sharifzadeh, Robert Gao, William S. Harmsen, Jason Klug, Panagiotis Korfiatis, Kimberly Gergelis, Dean A. Shumway, Robert Mutter, Kimberly Corbin. Sarcopenia and Post-Mastectomy Breast Reconstruction Outcomes after Radiation Therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-52.

In an era of increased political polarization, it is important to measure how receptive US American citizens are to diverse political views. Being more open to diverse political viewpoints—openness to political pluralism—may involve holding emotional and intellectual tolerance, non-rigidity, and proactive motivation to seek out different political perspectives. In three preregistered studies of US residents, we present a new self-report measure of openness to political pluralism (OPP) consisting of 25 items. In Study 1 (MTurk n = 400), we verified a preregistered bifactor model with four facets, conducted initial validity analyses, and created a short five-item version (OPPS). Both OPP and OPPS have high internal consistency and test-retest reliability. In Studies 2 and 3, MTurk participants (n = 258) and Qualtrics panel participants (n = 296) completed OPP and measures of related constructs to validate our scale. OPP was modestly correlated with actively open-minded thinking (AOT) and highly correlated with open-minded cognition-political (OMC-P). Greater OPP was associated with an inverted U-shape relation to left-right political orientation. It was also correlated with more politically diverse social networks and varied information seeking. We discuss how our measure of openness to political pluralism can be used in future research.

Critical approaches to logistics, in dialogue with geography and related disciplines, have exposed the turbulence behind apparently seamless transnational circulations of stuff. As everyday urban life becomes increasingly structured through logistical practices and expectations which imbricate consumption and distribution, now is an appropriate moment to take stock of these dialogues. Reviewing them, the article identifies three spatial assumptions – peripheral geographies, seamless consumption, forward motion – proposing that they express an additive, forward-leaning representation of logistics. In response, it draws upon debates on ‘negativity’ to suggest geographers pay greater attention to logistics’ negative spaces (voids), affects (dis-appointments) and mobilities (reversals).

The bacteria known as Uropathogenic Escherichia coli (UPECs) play a major role in triggering UTIs (UTIs). Antibiotic resistanceamong UPEC strains may progress faster if UTIs in Anbar continue to be treated with beta-lactam antibiotics without antibioticsusceptibility testing. In a study evaluating cephalosporin-resistance among 141 E. coli clinical isolates, 100 were found in urinesamples. Antibiotic resistance was analyzed using the VITEK-2 system. The results indicated that resistant to most β-lactamases usedin this study was associated with biofilm formation. 88.5% of UPEC isolates that showed biofilm positive were resist to 3rd generationcephalosporins with a statistically highly significance (P=

This study aimed to identification of genotypic characterization of lifA and fimH genes in 30 Enteropathogenic E.coli (EPEC) isolated from children suffering from diarrhea using Polymer Chain Reaction (PCR) technique. The results of agarose gel electrophoresis of lifA and fimH amplicons showed that 19(63%) and 25(83%) isolates were possess these gene respectively.Conclusions: There were high incidence of fimH and lifA genes in EPEC isolated from children suffering from diarrhea.

Inflammatory breast cancer (IBC) poses a radiotherapeutic challenge due to dermal lymphatic involvement, which often necessitates larger target volumes and chest wall boosts, making advanced planning techniques attractive to reduce exposure to nearby organs. We report our experience with intensity modulated proton therapy (IMPT) for the treatment of IBC.Between 2016 and 2020, all IBC patients treated with adjuvant IMPT at our institution were identified. Overall survival (OS) and distant metastasis-free survival (DMFS) were estimated using the Kaplan-Meier method. Adverse events (AEs) were assessed using CTCAE version 5.0.Nineteen patients were identified with median 24-month follow-up. CTVs included skin, chest wall, and regional lymph nodes. Median dose was 50 Gy in 25 fractions, with fifteen receiving chest wall boost (median 56.25 Gy in 25 fractions). During treatment, plan re-optimization was required in 9 (47%). Acute grade 3 dermatitis occurred in 2 (11%). Rib facture occurred in 4 (21%). One patient with pre-existing surgical seroma experienced a grade 3 fistula. Mean heart, left anterior descending artery, and right coronary artery doses were 0.7 Gy, 2.3 Gy, and 0.1 Gy, respectively. Mean ipsilateral lung V20Gy was 14.9%. At 2 years, there were no locoregional recurrences, and OS and DMFS were 89% and 82%, respectively.IMPT for IBC is well-tolerated with excellent dosimetry, low rates of AEs, and favorable early locoregional control outcomes. Follow-up for long-term outcomes is ongoing. Our findings suggest that IMPT is feasible and an attractive modality worthy of further investigation in patients with IBC.

Purpose: Triple-negative invasive lobular carcinoma (TN-ILC) of breast cancer is a rare disease and the clinical outcomes and prognostic factors are not well-defined. Methods: Women with stage I-III TN-ILC or triple-negative invasive ductal carcinoma (TN-IDC) of the breast undergoing mastectomy or breast-conserving surgery between 2010 and 2018 in the National Cancer Database were included. Kaplan-Meier curves and multivariate Cox proportional hazard regression were used to compare overall survival (OS) and evaluate prognostic factors. Multivariate logistic regression was performed to analyze the factors associated with pathological response to neoadjuvant chemotherapy. Results: The median age at diagnosis for women with TN-ILC was 67 years compared to 58 years in TN-IDC (pConclusion: Women with TN-ILC are older at diagnosis but have similar OS compared to TN-IDC after adjusting for tumor and demographic characteristics. Administration of chemotherapy was associated with improved OS in TN-ILC, but women with TN-ILC were less likely to achieve complete response to neoadjuvant therapy compared to TN-IDC.

The core metabolic reactions of life drive electrons through a class of redox protein enzymes, the oxidoreductases. The energetics of electron flow is determined by the redox potentials of organic and inorganic cofactors as tuned by the protein environment. Understanding how protein structure affects oxidation-reduction energetics is crucial for studying metabolism, creating bioelectronic systems, and tracing the history of biological energy utilization on Earth. We constructed ProtReDox ([https://protein-redox-potential.web.app](https://protein-redox-potential.web.app)), a manually curated database of experimentally determined redox potentials. With over 500 measurements, we can begin to identify how proteins modulate oxidation-reduction energetics across the tree of life. By mapping redox potentials onto networks of oxidoreductase fold evolution, we can infer the evolution of electron transfer energetics over deep-time. ProtReDox is designed to include user-contributed submissions with the intention of making it a valuable resource for researchers in this field.

The structure of the magmatic system beneath subaerial volcanos, including the architecture and distribution of the bodies where magma is stored and the network of conduits that transport melt between these accumulations and the surface, plays a fundamental role in all aspects of volcano construction and evolution, from igneous differentiation to hazard assessment. However, due to inaccessibility, little is known about the geometry of the magma bodies residing beneath subaerial volcanos. Mid-ocean ridges host the most extensive magmatic system on Earth, with 98% of its length below the ocean surface, which makes them an ideal target to be scanned by controlled-source marine seismic techniques. Beneath some portions of this vast system, the shallowest magma bodies are present and represented by long-linear Axial Magma Lenses (AML). It is at these shallow-most AMLs where dikes nucleate and connect the magma accumulations to the surface to result in an eruption. To explore the magma plumbing systems at mid-ocean ridges, we use 3-D multichannel seismic data across a mid-ocean ridge environment and apply advanced marine seismic techniques to develop the highest resolution reflection images of the AMLs so far. The data were collected across a magmatically dynamic portion of the East Pacific Rise at 9°50’N with documented dike intrusion and eruptions in 1991/1992 and 2005/06.The observations indicate that the magma reservoirs in the shallow crust are not represented by smooth bodies, but show strongly lineated topography that is spatially linked to the distribution of eruptive fissures and erupted lavas above. In the detailed topography, we find evidence for: 1) a dike root zone beneath where a caldera-like axial eruptive fissure zone is present, 2) deep excavation of this root zone within the primary eruption site for the last documented eruption, and 3) dikes rupturing from edges as well as the center of magma lenses. We also demonstrate that the distribution of additional, off-axis crustal magma accumulations further impact the stresses and melt budget at shallow-level magma accumulations leading to more frequent eruptions. Our results show that the mechanism behind eruptions along mid-ocean ridges is predominantly bottom-up and not fundamentally different from the eruptions’ mechanism at subaerial volcanoes. Considering the fine-scale morphology of shallow magma bodies will be critical for future generations of more realistic numerical models to aid in effective global volcanic hazard assessment and mitigation.

We develop a theory describing the transient transmission through noisy qubit-resonator systems with quadratic interactions as are found in superconducting and nanomechanical resonators coupled to solid-state qubits. After generalizing the quantum Langevin equations to arbitrary qubit-resonator couplings, we show that only the cases of linear and quadratic couplings allow for an analytical treatment within standard input-output theory. Focussing for the first time on quadratic couplings and allowing for arbitrary initial qubit coherences, it is shown that noise characteristics can be extracted from input-output measurements by recording both the averaged fluctuations in the transmission probability and the averaged phase. Our results represent an extension to the field of transmission-based noise spectroscopy with immediate practical applications., 8 pages, 3 figures

One of the recent advances in surgical AI is the recognition of surgical activities as triplets of (instrument, verb, target). Albeit providing detailed information for computer-assisted intervention, current triplet recognition approaches rely only on single frame features. Exploiting the temporal cues from earlier frames would improve the recognition of surgical action triplets from videos. In this paper, we propose Rendezvous in Time (RiT) - a deep learning model that extends the state-of-the-art model, Rendezvous, with temporal modeling. Focusing more on the verbs, our RiT explores the connectedness of current and past frames to learn temporal attention-based features for enhanced triplet recognition. We validate our proposal on the challenging surgical triplet dataset, CholecT45, demonstrating an improved recognition of the verb and triplet along with other interactions involving the verb such as (instrument, verb). Qualitative results show that the RiT produces smoother predictions for most triplet instances than the state-of-the-arts. We present a novel attention-based approach that leverages the temporal fusion of video frames to model the evolution of surgical actions and exploit their benefits for surgical triplet recognition., Accepted at IPCAI, 2023. Project Page: https://github.com/CAMMA-public/rendezvous-in-time

Supplementary Table 1 demonstrates single nucleotide variants, indels, copy number variants and copy number alterations in MCTNBC1

Supplementary Table 4 demonstrates single nucleotide variants, indels, copy number variants and copy number alterations in MCTNBC4

Supplementary Figure S1 demonstrates that VX-970 exhibits minimal single agent activity at the dose which radiosensitized TNBC cells.

Supplementary Figure S3 demonstrates median animal weights for the comparison of Sham, VX-970, RT, or the combination.

Triple-negative breast cancer (TNBC) is characterized by elevated locoregional recurrence risk despite aggressive local therapies. New tumor-specific radiosensitizers are needed. We hypothesized that the ATR inhibitor, VX-970 (now known as M6620), would preferentially radiosensitize TNBC. Noncancerous breast epithelial and TNBC cell lines were investigated in clonogenic survival, cell cycle, and DNA damage signaling and repair assays. In addition, patient-derived xenograft (PDX) models generated prospectively as part of a neoadjuvant chemotherapy study from either baseline tumor biopsies or surgical specimens with chemoresistant residual disease were assessed for sensitivity to fractionated radiotherapy, VX-970, or the combination. To explore potential response biomarkers, exome sequencing was assessed for germline and/or somatic alterations in homologous recombination (HR) genes and other alterations associated with ATR inhibitor sensitivity. VX-970 preferentially inhibited ATR-Chk1-CDC25a signaling, abrogated the radiotherapy-induced G2–M checkpoint, delayed resolution of DNA double-strand breaks, and reduced colony formation after radiotherapy in TNBC cells relative to normal-like breast epithelial cells. In vivo, VX-970 did not exhibit significant single-agent activity at the dose administered even in the context of genomic alterations predictive of ATR inhibitor responsiveness, but significantly sensitized TNBC PDXs to radiotherapy. Exome sequencing and functional testing demonstrated that combination therapy was effective in both HR-proficient and -deficient models. PDXs established from patients with chemoresistant TNBC were also highly radiosensitized. In conclusion, VX-970 is a tumor-specific radiosensitizer for TNBC. Patients with residual TNBC after neoadjuvant chemotherapy, a subset at particularly high risk of relapse, may be ideally suited for this treatment intensification strategy. Mol Cancer Ther; 17(11); 2462–72. ©2018 AACR.

Supplementary Table 3 demonstrates single nucleotide variants, indels, copy number variants and copy number alterations in MCTNBC3

Supplementary Figure S2 demonstrates individual tumor volume data of MCTNBC1, MCTNBC2, MCTNBC3, and MCTNBC4 for the experiment shown in figure 5.

Supplementary Table 2 demonstrates single nucleotide variants, indels, copy number variants and copy number alterations in MCTNBC2

Proton Bragg peak irradiation has a higher ionizing density than conventional photon irradiation or the entrance of the proton beam profile. Whether targeting the DNA damage response (DDR) could enhance vulnerability to the distinct pattern of damage induced by proton Bragg peak irradiation is currently unknown. Here, we performed genetic or pharmacologic manipulation of key DDR elements and evaluated DNA damage signaling, DNA repair, and tumor control in cell lines and xenografts treated with the same physical dose across a radiotherapy linear energy transfer spectrum. Radiotherapy consisted of 6 MV photons and the entrance beam or Bragg peak of a 76.8 MeV spot scanning proton beam. More complex DNA double-strand breaks (DSB) induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ataxia-telangiectasia mutated (ATM) inhibitor, AZD0156, but not an inhibitor of ATM and Rad3-related, rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more DSBs to processing by toxic ligation through nonhomologous end-joining, whereas loss of DNA ligation via XRCC4 or Lig4 knockdown rescued resection and abolished the enhanced Bragg peak cell killing. Proton Bragg peak monotherapy selectively sensitized cell lines and tumor xenografts with inherent HR defects, and the repair defect induced by ATM inhibitor coadministration showed enhanced efficacy in HR-proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR-proficient tumors selectively enhances the relative biological effectiveness of proton Bragg peak irradiation.Significance:Coadministration of an ATM inhibitor rewires DNA repair machinery to render cancer cells uniquely hypersensitive to DNA damage induced by the proton Bragg peak, which is characterized by higher density ionization.See related commentary by Nickoloff, p. 3156

This file contains tables showing the association between BMI and each of ER and PR when adjusted for both risk factors and prognostic factors; associations between BMI and each of ER and PR when a consistent BMI reference group of normal weight is used; and risk stratification tables for the prediction of endometrial cancer-specific mortality using dichotomous tumor ER or PR status.

Background: Endometrial tumors arise from a hormonally responsive tissue. Defining subtypes by hormone receptor expression might better inform etiology and prediction of patient outcomes. We evaluated the potential role of tumor estrogen receptor (ER) and progesterone receptor (PR) expression to define endometrial cancer subtypes.Methods: We measured semi-continuous ER and PR protein expression in tissue specimens from 360 endometrial primary tumors from the Nurses' Health Study. To explore the impact of different definitions of marker positivity, we dichotomized ER and PR expression at different cut points in increments of 5% positive cells. Logistic regression was used to estimate associations between endometrial cancer risk factors, such as body mass index, with dichotomous ER or PR status. Reclassification statistics were used to assess whether adding dichotomous ER or PR status to standard prognostic factors of stage, grade, and histologic type would improve endometrial cancer-specific mortality prediction.Results: Compared with not being obese, obesity increased the odds of having an ER-positive tumor at cut points of 0% to 20% [maximum OR, 2.92; 95% confidence interval (CI), 1.34–6.33] as well as the odds of having a PR-positive tumor at cut points of 70% to 90% (maximum OR, 2.53; 95% CI, 1.36–4.68). Adding dichotomous tumor ER or PR status to the panel of standard predictors did not improve both model discrimination and calibration.Conclusions: Obesity may be associated with greater endometrial tumor expression of ER and PR. Adding either marker does not appear to improve mortality prediction beyond the standard predictors.Impact: Body mass index might explain some of the biological variation among endometrial tumors. Cancer Epidemiol Biomarkers Prev; 26(5); 727–35. ©2017 AACR.

This file provides detailed information on immunohistochemistry assay protocols as well as on the analytic handling of missing covariate data.

Sporadic somatic inactivation of genes such as PTEN within histologically normal endometrium (latent precancers) is an early step in endometrial carcinogenesis. We have used clone-specific mutations of PTEN to determine the fate of latent precancers over time in women who do (high risk) and do not (low risk) develop endometrial neoplasia. PTEN immunohistochemistry was performed on 45 occurrences of endometrial neoplasia and their paired antecedent benign biopsies, along with age matched sample pairs from 167 patients who did not develop a neoplasm. When PTEN-deficient cells were present at both time points, DNA sequencing was performed to determine whether they were single or multiple independent events. Loss of PTEN protein in isolated glands was common in the initial normal biopsies of high- and low-risk groups (42% and 27%, respectively, P = 0.066). Protein-deficient glands have a tendency to disappear over time in low-risk women (P = 0.047) and, even when “persistent,” are infrequently (19%, 3/16) confirmed to be the same clone. Similarly, only a small proportion (6.7%, 1/15) of latent precancers seen in high-risk women are the direct progenitors of subsequent neoplasia. There is a high rate of latent precancer turnover in both low- and high-risk patients, with rare long-term persistence of unique clones, which may or may not progress to a histologic lesion. The temporal dynamics of clonal emergence, persistence, and involution are sufficiently complex that in the individual patient, the presence of a latent precancer has an unknown contribution to long-term cancer risk. Cancer Res; 74(10); 2796–802. ©2014 AACR.

Supplementary data and figure legends from Combined Total Genome Loss of Heterozygosity Scan of Breast Cancer Stroma and Epithelium Reveals Multiplicity of Stromal Targets

Latent endometrial carcinoma precancers are normal-appearing endometrial glands with sporadic loss of tumor suppressor gene function such as PTEN. Progression to carcinoma is inefficient and requires additional genetic damage that creates a histologic precursor lesion called endometrial intraepithelial neoplasia (EIN). In this study, we examined loss of PAX2 expression, a gene required for embryonic uterine development, during endometrial carcinogenesis. Normal proliferative, EIN, and malignant (endometrial adenocarcinoma) endometrial tissues were immunostained for PTEN and PAX2. Proliferative samples with loss of protein in at least one gland were scored as latent precancers. EIN and cancer lesions were scored by the majority pattern. Overall prevalence and topography of joint PAX2-PTEN expression loss was examined. The prevalence of PAX2 protein loss in the sequence of normal to precancer to cancer was 36%, 71%, and 77%, respectively, and for PTEN, it was 49%, 44%, and 68%, respectively. The normal endometrial prevalence of PAX2- or PTEN-deficient latent precancers was unaffected by biopsy indication, but increased significantly with age. Coincident loss of PAX2 and PTEN expression in an individual normal endometrium was seen in 21% of patients, but usually involved different glands. Coincident loss was more common in precancers (31%) and carcinoma (55%), in which case, both markers were protein null in an overlapping clonal distribution. PAX2 and PTEN protein loss occurs independently and accumulates with increasing age in latent precancers of normal premenopausal endometrium. Loss of function of both genes in an overlapping distribution characterizes the clinical emergence of a premalignant lesion which is carried forward to carcinoma. Cancer Res; 70(15); 6225–32. ©2010 AACR.

PDF file - 14KB, Supplementary Table 1. Mutation List for Pairmax paired protein null samples n = 31.

Recent breast cancer studies have highlighted the importance of interactions between cancer epithelium and tumor stroma. Recently, the focus of solid tumor investigations has shifted from mutations in carcinomatous epithelium to disturbances of tissue organization in cancer. The genetic basis of this microenvironment, however, remains to be clarified. To begin to resolve this problem, a total genome loss of heterozygosity (LOH) scan was done on epithelial and stromal DNA from 134 sporadic invasive breast carcinomas. In addition to detecting more frequent LOH at three loci in stroma than in epithelium, we found strong evidence that LOH frequencies were significantly elevated in specific regions of each chromosome. We detected 57 markers, which were preferentially lost either in stroma (n = 38) or epithelium (n = 19), relative to the background LOH frequencies on their respective chromosomes. This multiplicity of stromal cell LOH, and hence loss of genetic material, provides a possible mechanism for interpatient variation in host-stromal response to invading adenocarcinoma cells. This is consistent with a model in which initial, random LOH occurs equally among epithelium and stroma, but subsequent clonal selection is driven by factors, which appear to be distinctly different between malignant epithelial and surrounding stromal cells. Genetic alterations in stroma did not mimic those in epithelium, but they could play a different and parallel role in carcinogenesis and tumor progression, probably by modifying some features specific to breast cancer.

Supplementary Tables 1-2 from Joint Loss of PAX2 and PTEN Expression in Endometrial Precancers and Cancer

Supplementary Figure S1 from Combined Total Genome Loss of Heterozygosity Scan of Breast Cancer Stroma and Epithelium Reveals Multiplicity of Stromal Targets

This review-essay examines two books about the history of the modern humanities: Permanent Crisis: The Humanities in a Disenchanted Age by Paul Reitter and Chad Wellmon and Battle of the Classics: How a Nineteenth-Century Debate Can Save the Humanities Today by Eric Adler. Both studies reconstruct genealogies of discourse and practice by which to understand the “crisis” of the humanities, yet they draw disparate lessons from these reconstructions. The review traces the two monographs’ competing accounts of the historical continuity of humanities practices and the moral dimension of humanistic inquiry. Together, Permanent Crisis and Battle of the Classics describe an antinomy that can be neither resolved nor ignored: the methodological norms of the modern university tend to subvert the humanities’ investment in meaning and value, but without that investment, humanistic study loses the motivations and purposes that define it.

Ruptured abdominal aortic aneurysm (rAAA) is a life-threatening condition, and rapid diagnosis is necessary to facilitate early surgical intervention. We sought to evaluate the accuracy of presenting symptoms, physical examination signs, computed tomography with angiography (CTA), and point-of-care ultrasound (PoCUS) for diagnosis of rAAA.We searched six databases from inception through April 2021. We included studies investigating the accuracy of any of the above tests for diagnosis of rAAA. The primary reference standard used in all studies was intraoperative diagnosis or death from rAAA. Because PoCUS cannot detect rupture, we secondarily assessed its accuracy for the diagnosis of AAA, using the reference standard of intraoperative or CTA diagnosis. We used GRADE to assess certainty in estimates.We included 20 studies (2,077 patients), with 11 of these evaluating signs and symptoms, seven evaluating CTA, and five evaluating PoCUS. Pooled sensitivities of abdominal pain, back pain, and syncope for rAAA were 61.7%, 53.6%, and 27.8%, respectively (low certainty). Pooled sensitivity of hypotension and pulsatile abdominal mass were 30.9% and 47.1%, respectively (low certainty). CTA had a sensitivity of 91.4% and specificity of 93.6% for diagnosis of rAAA (moderate certainty). In our secondary analysis, PoCUS had a sensitivity of 97.8% and specificity of 97.0% for diagnosing AAA in patients suspected of having rAAA (moderate certainty).Classic clinical symptoms associated with rAAA have poor sensitivity, and their absence does not rule out the condition. CTA has reasonable accuracy, but misses some cases of rAAA. PoCUS is a valuable tool that can help guide the need for urgent transfer to a vascular center in patients suspected of having rAAA.