Treating triple-negative breast cancer by a combination of rapamycin and cyclophosphamide: An in vivo bioluminescence imaging study

Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to inhibit the growth of oestrogen positive breast cancer. However, triple-negative (TN) breast cancer is resistant to rapamycin treatment in vitro. We set to test a combination treatment of rapamycin with DNA-damage agent, cyclophosphamide, in a TN breast cancer model. By binding to and disrupting cellular DNA, cyclophosphamide kills cells via interfering with their normal functions. We assessed the responses of nude mice bearing tumour xenografts of TN MDA-MB-231 cells to the combination of rapamycin and cyclophosphamide in both orthotopic mammary and lung-metastasis models. We tracked tumour growth and metastasis by bioluminescent imaging and examined the expression of Ki67, CD34 and HIF-1α in tumour tissues by immunohistochemistry and apoptosis index with TUNEL assay, and found that MDA-MB-231 cells are sensitive to rapamycin therapy in orthotopic mammary, but not in lung with metastasis. Rapamycin when combined with cyclophosphamide is found to have a more significant effect in reducing tumour volume and metastasis with a much improved survival rate. Our data also show that the sensitivity of TN tumours to rapamycin is associated with the microenvironment of the tumour cells. The data indicate that in a relatively hypoxic environment HIF-1α may play a role in mediating the anti-cancer effect of rapamycin and cyclophosphamide may prevent the feedback activation of Akt by rapamycin. Overall our results show that rapamycin plus cyclophosphamide can achieve an improved efficacy in suppressing tumour growth and metastasis, suggesting that the combination therapy can be a promising treatment option for TN cancer.     

Structures,processes and outcomes of objective structured clinical examinations in dental education during the COVID-19 pandemic: A scoping review

Introduction

Objective structured clinical examinations (OSCEs) are an essential examination tool within undergraduate dental education. Fear of spread of the COVID-19 virus led to dental institutions exploring alternative means of conducting OSCEs. The aim of this scoping review was to investigate what structures, processes and outcomes of dental OSCEs were reported during the COVID-19 pandemic.

Materials and Methods

This scoping review was conducted and reported adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping review guidelines (PRISMA-ScR). Published literature was identified through a systematic search of PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Education Resources Information Center (Eric), ProQuest and Google Scholar. Identified articles were independently reviewed by two authors (KS, AD), followed by synthesis in terms of the reported structures, processes and outcomes. Articles reporting cancellation or rescheduling were also included, extracting data on reasons and any suggestions/recommendations.

Results

The search yielded a total of 290 studies of which 239 sources were excluded after removal of duplicates, leaving 51 studies for title and abstract evaluation. Thirty-four articles were excluded as they did not report on the topic of interest, leaving 17 for full-text evaluation, of which nine were analysed according to the pre-set themes. All dental OSCEs taking place (n = 6) were conducted online whilst the remaining (n = 3) were either cancelled or rescheduled. Data on structures reported specific online videoconferencing software used and provision of staff and student training. Processes on the execution of online OSCEs varied significantly from one study to the other, providing rich data on how dental institutions may carry out such assessments tailored to their need. Information regarding outcomes was sparse, as little attention was paid to the results of the students compared to pre-pandemic, lacking investigation into reliability and validity of online dental OSCEs.

Conclusion

Dental OSCEs could be conducted online implementing well-planned structures and processes; however, further evidence is needed to prove its reliability and validity based on outcomes. Dental institutions may need to consider alternative methods to assess practical competencies if online OSCEs are to take place.     

Associations between Race/Ethnicity,Uterine Fibroids,and Minimally Invasive Hysterectomy in the VA Healthcare System

Background

In the general population, Black and Latina women are less likely to undergo minimally invasive hysterectomy than White women, which may be related to racial/ethnic variation in fibroid prevalence and characteristics. Whether similar differences exist in the Department of Veterans Affairs Healthcare System (VA) is unknown.

Surgeon Volume and Outcomes in Benign Hysterectomy

Annual surgeon case volume has been linked to patient outcome in a variety of surgical fields, although limited data focus on gynecologic surgery performed by general gynecologists. Herein we review the literature addressing the associations between intraoperative injury, postoperative morbidity, and resource use among surgeons performing a low vs high volume of hysterectomies. Although study design and populations differ, individual and composite morbidity outcomes consistently favored high-volume surgeons. Given the growing emphasis on competency-based evaluation in surgery, gynecology departments may soon consider volume requirements a component of privileging.     

近视与糖尿病视网膜病变的相关性

目的：利用双眼糖尿病视网膜病变（DR）程度的不对称性探讨近视与DR的相关性。方法：横断面研 究。根据糖尿病早期治疗研究（ETDRS）标准,将抚顺糖尿病视网膜病变队列研究的患者进行DR与 糖尿病性黄斑水肿（DME）分级。DR分级包括无DR、轻度非增殖性DR（NPDR）、中度NPDR、重度 NPDR与增殖性DR（PDR）。纳入双眼DR程度至少相差1级（314例,628眼）或仅单眼DME（74例, 148眼）的患者共388例（776眼）。近视与高度近视分别定义为等效球镜度（SE）<-1 D与<-5 D。采 用配对t检验比较较好眼与较差眼间SE的差异,采用McNemar配对检验比较较好眼与较差眼间近视 及高度近视比例的差异。结果：388例患者年龄（60.6±8.5）岁,其中男147例（37.9%）。双眼DR程 度大多数相差1级（297例,76.5%）。较好眼的SE较对侧眼偏负[（-0.22±2.24）D与（0.00±1.95）D, t=3.01,P=0.003],较好眼高度近视比例高于对侧眼（4.4%与2.1%,χ2 =6.23,P=0.01）。按较好眼 DR程度分组后,NPDR患者较好眼的SE较对侧眼偏负[（-0.37±2.76）D与（0.14±1.89）D,t=2.57, P=0.01],高度近视比例高于对侧眼（7.8%与1.1%,χ2 =6.00,P=0.01）。无DR患者以及DME患者中, 较好眼与较差眼间各屈光参数差异均无统计学意义。结论：本研究利用双眼DR程度的不对称性,证 实了高度近视与DR的负相关关系。     

Distinct ongoing Ig heavy chain rearrangement processes in childhood B- precursor acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is thought to arise from the clonal expansion of a single transformed precursor cell. However, an oligoclonal Ig heavy chain (IgH) rearrangement pattern has been observed in 30% of ALL patients and was shown to be the result of ongoing rearrangement events. The extent and nature of these ongoing rearrangement processes in individual patients has so far remained obscure. We performed a detailed analysis of leukemic VHDJH rearrangements in three children with B-precursor ALL at diagnosis and one B-lymphoid blast crisis of a child with Ph+ chronic myeloid leukemia at diagnosis and relapse. The children were selected because they presented with multiple IgH rearrangements on Southern blot analysis. Polymerase chain reaction analysis of leukemic cells from two B-precursor ALL patients showed exclusively two groups of related sequences resulting from VH gene replacement events. Most VH gene replacements involved 3' located acceptor VH genes. Analysis of cells from the other B-precursor ALL patient showed exclusively related sequences as a result of VH gene joinings to a pre-existing DJH rearrangement. In the B-lymphoid blast crisis, a single germline precursor cell had generated multiple unrelated rearrangements and additional groups of related rearrangements resulting from VH to DJH joinings. Direct proof for the VH to DJH joining mechanism was obtained by amplification of the expected preexisting DJH rearrangements. Our findings suggest that the pattern of ongoing rearrangements in an individual patient reflects the IgH rearrangement status of the precursor cell at the time of malignant transformation. Sequence analysis of VHDJH rearrangements at diagnosis may therefore allow a prediction of the reliability of complementarity determining region 3 probes for the detection of minimal residual disease.     

Regulation of inflammation by lipid mediators in oral diseases

Lipid mediators (LM) of inflammation are a class of compounds derived from ω‐3 and ω‐6 fatty acids that play a wide role in modulating inflammatory responses. Some LM possess pro‐inflammatory properties, while others possess proresolving characteristics, and the class switch from pro‐inflammatory to proresolving is crucial for tissue homeostasis. In this article, we review the major classes of LM, focusing on their biosynthesis and signaling pathways, and their role in systemic and, especially, oral health and disease. We discuss the detection of these LM in various body fluids, focusing on diagnostic and therapeutic applications. We also present data showing gender‐related differences in salivary LM levels in healthy controls, leading to a hypothesis on the etiology of inflammatory diseases, particularly Sjögren's syndrome. We conclude by enumerating open areas of research where further investigation of LM is likely to result in therapeutic and diagnostic advances.     

Systemic lupus erythematosus in three ethnic groups. X. Measuring cognitive impairment with the cognitive symptoms inventory

OBJECTIVE: To determine the factor structure of the Cognitive Symptoms Inventory (CSI) in patients with systemic lupus erythematosus (SLE) participating in a multiethnic longitudinal study of outcome, the Lupus in Minority populations, Nature versus nurture (LUMINA) study.METHODS: LUMINA patients of Hispanic (n = 48), African American (n = 64), and Caucasian (n = 44) ethnicity who had a study visit (enrollment or followup) between January 1 and September 30, 2000 were included. Patients completed the CSI, a 21-item self-report measure of cognitive function. Sociodemographic, clinical, immunologic, psychosocial, and behavioral variables were ascertained per protocol and as previously described. Data were analyzed with SPSS. The factor structure of the CSI was determined using the principal axis method with oblique rotation as decided by Gorsuch. All factors having an Eigenvalue greater than 1 were considered. A 4-factor solution was derived that accounted for 42.6% of the common variance. The correlations between patient factor scale scores and variables from the demographic, clinical, psychosocial, and behavioral domains were then examined.RESULTS: The four factors and their respective variance are, Attention/Concentration (28.8%), Pattern Recognition/Activity Management (5.7%), Intermediate Memory (4.7%), and Initiation of Executive Functions (3.4%); each factor correlated with the total CSI score. Overall, patients' factor scale scores were positively and significantly correlated with other measures of cognitive dysfunction such as the Systemic Lupus Activity Measure (neuromotor domain) or the Systemic Lupus International Collaborating Clinics Damage Index (neurocognitive impairment), as well as with measures of fatigue, maladaptive coping skills, poor mental functioning, poor social support, and helplessness. They were, however, not correlated with sociodemographic or clinical variables.CONCLUSIONS: In addition to demonstrating that the CSI can be used to measure cognitive impairment in patients with SLE in the research setting, we have determined a 4-factor solution for the CSI that appears to have adequate metric properties. At present, the CSI may best be used as a screen for difficulties in daily activities involving intermediate memory, concentration, attention, and executive function. Nevertheless, further work with the CSI items and factor scales is necessary to establish internal and test-retest reliability of the factor scales; and provide additional evidence of the convergent and predictive validity of these scales in larger samples of patients from each ethnic subgroup.