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Objective: The diagnostic criteria of lymphatic vascular invasion have not been standardized. Our investigation assesses the factors associated with lymphatic vascular invasion positive tumors and the impact of lymphatic vascular invasion on overall survival for patients with non–small cell lung cancer undergoing (bi)lobectomy with an adequate node dissection. Methods: The National Cancer Database was queried from the years 2010 to 2015 to find surgical patients who underwent lobectomy with at least 10 lymph nodes examined (adequate node dissection) and with known lymphatic vascular invasion status. Paired t tests were used to distinguish differences between the patients with and without lymphatic vascular invasion in their specimen. Multivariable analysis was used to determine factors associated with overall survival. Propensity score matching adjusting for overall survival factors was used to determine the lymphatic vascular invasion's overall survival impact by grade, histology, p-T/N/overall stage, and tumor size. Results: Lymphatic vascular invasion status was reported in 91.6% and positive in 23.4% of 28,842 eligible patients. Academic medical centers, institutions with populations more than 1,000,000, and the mid-Atlantic region reported higher rates of lymphatic vascular invasion positive tumors as well as overall survival compared with other cancer centers. Lymphatic vascular invasion was independently associated with a significant decrement in overall survival as per multivariable analysis and propensity score matching. Propensity score matching demonstrated that lymphatic vascular invasion was associated with a significant decrement in overall survival for all histologies, tumor grades, tumor sizes, and stages, except for more advanced pathologic stages T3/III/N2 and larger tumors greater than 4 cm for which overall survival was trending worse with lymphatic vascular invasion positive. Conclusions: Lymphatic vascular invasion positive varies based on hospital location/type and population, but it was associated with a decrement in overall survival that was independent of pathologic T/N/overall stage, histology, and tumor grade. Lymphatic vascular invasion must be standardized and considered as a staging variable and should be considered as a sole determinant for prognosis, especially for those with earlier-stage and smaller tumors.

Summary: Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.

Background: Inadequate pain control after lung transplantation increases perioperative complications. Standard opioid-based regimens are associated with adverse effects and epidural catheters that reduce opioid use are limited by contraindications and technical challenges. We report the use of intercostal nerve cryoablation to enhance perioperative pain control as part of an opioid-sparing protocol for lung transplant recipients (LTR). Methods: We conducted a retrospective cohort study of LTRs from January 1, 2016 to December 31, 2021, before (precryo) and after (postcryo) initiation of an opioid-sparing protocol utilizing intraoperative intercostal nerve cryoablation. The precryo cohort included consecutive patients treated with opioids and selective use of epidural catheters. The postcryo cohort received intercostal nerve cryoablation at levels 3 to 7, scheduled acetaminophen, gabapentin, and tramadol. Additional opioids or epidural catheters were used for breakthrough pain. Results: In total, 49 precryo and 40 postcryo patients were analyzed. Baseline demographics were similar aside from a shift to performing more bilateral lung transplants in the postcryo cohort (57% vs 95%, p

Abstract In their paper “Challenges with international medical graduate selection: finding positive attributes predictive of success in family medicine residency,” (BMC Prim Care 23(256):2–9, 2022) the authors report on their research into qualitative attributes that positively correspond to success in residency with the objective of assisting in the selection of International Medical Graduate (IMG) residents most likely to achieve success in family medicine residency. The authors found that positive predictors of IMG residents’ success were: presence of a positive attitude, proficient communication skills, high level of clinical knowledge, and trainability. The authors conclude that selecting IMG residents who possess these attributes will result in residents developing increased aptitudes for patient care. A careful reading of the paper raises a number of concerns. MacFarlane (Can Med Educ J 12(4):132–40, 2021) points out that IMGs are already marginalized in the residency selection process. Our concern is that this paper may contribute to this marginalization through a tone of negativity or bias against IMGs and the use of biased language throughout the paper that tends to cast IMGs as being inferior and somehow less well prepared for residency than Canadian Medical Graduates (CMGs). We argue that the proposed predictors are generic and equally relevant to both CMGs and IMGs. In focusing on these predictors in IMGs specifically, the paper appears to imply, without evidence, that IMGs are inadequate in the identified areas. After reviewing the paper’s references, the existing literature, and an analysis of language used, we conclude that IMGs are capable candidates for residency, and that the qualitative attributes outlined in the paper offer little utility for the selection of IMG residents relative to CMG residents.

Retinal sensitivity to a variety of artificial sweeteners was tested by monitoring changes in internal free calcium in isolated retinal neurons using Fluo3. Several ligands, including aspartame and saccharin elevated internal free calcium. The effects of these ligands were mediated by both ligand-gated membrane channels and G-protein coupled receptors. We explored the receptors responsible for this phenomenon. Surprisingly, mRNA for subunits of the sweet taste receptor dimer (T1R2 and T1R3) were found in retina. Interestingly, knockdown of T1R2 reduced the response to saccharin but not aspartame. But TRPV1 channel antagonists suppressed the responses to aspartame. The results indicate that artificial sweeteners can increase internal free calcium in the retinal neurons through multiple pathways. Furthermore, aspartame reduced the b-wave, but not the a-wave, of the electroretinogram, indicating disruption of communication between photoreceptors and second order neurons.

Challenges such as backhaul availability and backhaul scalability have continued to outweigh the progress of integrated access and backhaul (IAB) networks that enable multi-hop backhauling in 5G networks. These challenges, which are predominant in poor wireless channel conditions such as foliage, may lead to high energy consumption and packet losses. It is essential that the IAB topology enables efficient traffic flow by minimizing congestion and increasing robustness to backhaul failure. This article proposes a backhaul adaptation scheme that is controlled by the load on the access side of the network. The routing problem is formulated as a constrained Markov decision process and solved using a dual decomposition approach due to the existence of explicit and implicit constraints. A deep reinforcement learning (DRL) strategy that takes advantage of a recursive discrete choice model (RDCM) was proposed and implemented in a knowledge-defined networking architecture of an IAB network. The incorporation of the RDCM was shown to improve robustness to backhaul failure in IAB networks. The performance of the proposed algorithm was compared to that of conventional DRL, i.e., without RDCM, and generative model-based learning (GMBL) algorithms. The simulation results of the proposed approach reveal risk perception by introducing certain biases on alternative choices and the results showed that the proposed algorithm provides better throughput and delay performance over the two baselines.

Abstract LIM domain-binding 3 (LDB3) is a member of the Enigma family of PDZ–LIM proteins. LDB3 has been reported as a striated muscle-specific Z-band alternatively spliced protein that plays an important role in mechanosensory actin cytoskeleton remodeling. This study shows that LDB3 is broadly expressed in the central and peripheral nervous system of human and mouse. LDB3 is predominantly expressed in the adult stages compared to early development and at a significantly higher level in the spinal cord than in the brain. As in skeletal muscle and heart, LDB3 is extensively alternatively spliced in the neurons. Three novel splice isoforms were identified suggesting splicing-dependent regulation of LDB3 expression in the nervous system. Expression of LDB3 in the motor cortex, cerebellum, spinal motor neuron, peripheral nerve, and neuromuscular junction in addition to skeletal muscle indicates important roles for this PDZ–LIM family protein in motor planning and execution. Moreover, expression in the hippocampal neurons suggests roles for LDB3 in learning and memory. LDB3 interactors filamin C and myotilin are also expressed in the spinal motor neuron, nerve, and neuromuscular junction, thereby providing the basis for neurogenic manifestations in myopathies associated with mutations in these so-called muscle proteins.

ObjectiveWe investigated the impact of body mass index (BMI) on post-operative outcomes and survival of patients with interstitial pulmonary fibrosis (IPF) undergoing lung transplantation.MethodsWe retrospectively reviewed 222 patients with IPF that underwent lung transplant (LT) at our institution from 2005 to 2019. Recipients were divided in 4 groups: group-1 consisted of underweight patients (BMI ≤18.5 kg/m2), group-2 of normal weight patients (BMI 18.5–25 kg/m2), group-3 of over-weight patients (BMI 25–29.9 kg/m2) and group-4 of obese patients (BMI ≥30 kg/m2).ResultsGroup-1 consisted of 13 (6%) patients, group-2 of 67 (30%) patients, group-3 of 79 (36%) patients, group-4 consisted of 63 (28%) patients. Median BMI for group-1 was 17 [interquartile range (IQR): 17, 18], for group-2 was 23 (22, 24), for group-3 was 29 (28, 29.5) and group-4 was 32 (31, 33). Patients in group-1 were significantly younger (p 0.05). Overall reasons for death included graft failure (24%), infection (23%), respiratory failure (14%), and malignancy (13%).ConclusionsBody mass index does not impact long-term survival of patients with IPF undergoing lung transplantation.

A transgenic mouse approach using bacterial artificial chromosomes (BAC) was used to identify regulatory regions that direct Müllerian duct expression for Amhr2 and Osterix (Osx, also known as Sp7). Amhr2 encodes the receptor that mediates anti-Müllerian hormone (AMH) signaling for Müllerian duct regression in male embryos. Amhr2 is expressed in the Müllerian duct mesenchyme of both male and female embryos. A ∼147-kb BAC clone containing the Amhr2 locus was used to generate transgenic mice. The transgene was able to rescue the block in Müllerian duct regression of Amhr2-null males, suggesting that the BAC clone contains regulatory sequences active in male embryos. Osx is expressed in the developing skeleton of male and female embryos but is also an AMH-induced gene that is expressed in the Müllerian duct mesenchyme exclusively in male embryos. Osx-Cre transgenic mice were previously generated using a ∼204-kb BAC clone. Crosses of Osx-Cre mice to Cre-dependent lacZ reporter mice resulted in reporter expression in the developing skeleton and in the Müllerian duct mesenchyme of male but not female embryos. Osx-Cherry transgenic mice were previously generated using a 39-kb genomic region surrounding the Osx locus. Osx-Cherry embryos expressed red fluorescence in the developing skeleton and Müllerian duct mesenchyme of male but not female embryos. In addition, female Osx-Cherry embryos ectopically expressing human AMH from an Mt1-AMH transgene activated red fluorescence in the Müllerian duct mesenchyme. These results suggest that the 39-kb region used to generate Osx-Cherry contains male-specific Müllerian duct mesenchyme regulatory sequences that are responsive to AMH signaling. These BAC transgenic mouse approaches identify two distinct regions that direct Müllerian duct mesenchyme expression and contribute fundamental knowledge to define a gene regulatory network for sex differentiation.

Abstract Background Irreversible electroporation (IRE) is a local ablation technique utilizing high voltage, low energy direct current to create nanopores in cell membrane which disrupt homeostasis and leads to cell death. Previous reports have suggested IRE may have a role in treating borderline resectable and unresectable Stage 3 pancreatic tumors. Methods Patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) will be enrolled in either a randomized, controlled, multicenter trial (RCT) or a multicenter registry study. Subjects enrolled in the RCT must have no evidence of disease progression after 3 months of modified FOLFIRINOX (mFOLFIRINOX) treatment prior to being randomization to either a control or IRE arm. Post-induction and post-IRE treatment for the control and IRE arms, respectively, will be left to the discretion of the treating physician. The RCT will enroll 528 subjects with 264 per arm and include up to 15 sites. All subjects will be followed for at least 24 months or until death. The registry study will include two cohorts of patients with Stage 3 PDAC, patients who received institutional standard of care (SOC) alone and those treated with IRE in addition to SOC. Both cohorts will be required to have undergone at least 3 months of SOC without progression prior to enrollment. The registry study will enroll 532 patients with 266 patients in each arm. All patients will be followed for at least 24 months or until death. The primary efficacy endpoint for both studies will be overall survival (OS). Co-primary safety endpoints will be 1) time from randomization or enrollment in the registry to death or new onset of Grade 4 adverse event (AE), and (2 high-grade complications defined as any AE or serious AE (SAE) with a CTCAE v5.0 grade of 3 or higher. Secondary endpoints will include progression-free survival, cancer-related pain, quality of life, and procedure-related pain for the IRE arm only. Discussion These studies are intended to provide Level 1 clinical evidence and real-world data demonstrating the clinical utility and safety of the use of IRE in combination with chemotherapy in patients with Stage 3 PDAC. Trial registration Clinicaltrials.gov NCT03899636 and NCT03899649. Registered April 2, 2019. Food and Drug Administration (FDA) Investigational Device Exemption (IDE) trial G180278 approved on May 3, 2019.

Congestion in dense traffic networks is a prominent obstacle towards realizing the performance requirements of 5G new radio. Since traditional adaptive traffic signal control cannot resolve this type of congestion, realizing context in the network and adapting resource allocation based on real-time parameters is an attractive approach. This article proposes a radio resource management solution for congestion avoidance on the access side of an integrated access and backhaul (IAB) network using deep reinforcement learning (DRL). The objective of this article is to obtain an optimal policy under which the transmission throughput of all UEs is maximized under the dictates of environmental pressures such as traffic load and transmission power. Here, the resource management problem was converted into a constrained problem using Markov decision processes and dynamic power management, where a deep neural network was trained for optimal power allocation. By initializing a power control parameter, $\theta _{t}$ , with zero-mean normal distribution, the DRL algorithm adopts a learning policy that aims to achieve logical allocation of resources by placing more emphasis on congestion control and user satisfaction. The performance of the proposed DRL algorithm was evaluated using two learning schemes, i.e., individual learning and nearest neighbor cooperative learning, and this was compared with the performance of a baseline algorithm. The simulation results indicate that the proposed algorithms give better overall performance when compared to the baseline algorithm. From the simulation results, there is a subtle, but critically important insight that brings into focus the fundamental connection between learning rate and the two proposed algorithms. The nearest neighbor cooperative learning algorithm is suitable for IAB networks because its throughput has a good correlation with the congestion rate.

Alcohols are more naturally abundant than carbonyl compounds, which in turn are well known for their reactivity in Grignard reactions. Here, the authors showcase a distinct Grignard-like reactivity by using alcohols as coupling partners with hydrazones and synthesize more complex alcohols under ruthenium catalysis.

This paper explores the marginalization experienced by International Medical Graduates (IMGs) in the Canadian Residency Matching Service (CaRMS) Match. This marginalization occurs despite all IMGs being Canadian citizens or permanent residents, and having objectively demonstrated competence equivalent to that expected of a graduate of a Canadian medical School through examinations such as the MCCQE1 and the National Assessment Collaboration OSCE. This paper explores how the current CaRMS Match works, evidence of marginalization, and ethnicity and human rights implications of the current CaRMS system. A brief history of post graduate medical education and the residency selection process is provided along with a brief legal analysis of authority for making CaRMS eligibility decisions. Current CaRMS practices are situated in the context of Provincial fairness legislation, and rationalizations and rationales for the current CaRMS system are explored. The paper examines objective indicators of IMG competence, as well as relevant legislation regarding international credential recognition and labour mobility. The issues are placed in the context of current immigration and education policies and best practices. An international perspective is provided through comparison with the United States National Residency Matching Program. Suggestions are offered for changes to the current CaRMS system to bring the process more in line with legislation and current Canadian value systems, such that “A Canadian is a Canadian.”

Abstract Background Foam rolling (FR) has been shown to alleviate some symptoms of exercise-induced muscle damage and has been suggested to increase range of motion (ROM) without negatively impacting strength. However, it is unclear what neuromuscular effects, if any, mediate these changes. Methods In a randomized, crossover design, 16 healthy active males completed 2 min of rest or FR of the knee extensors on three consecutive days. Mechanical properties of vastus lateralis (VL) and rectus femoris (RF) were assessed via Tensiomyography. Knee extension maximal voluntary contraction (MVC) and knee flexion ROM were also assessed, and surface electromyography amplitude (RMS) was recorded during a submaximal isometric contraction (50% of MVC). Measures were performed before and after (0, 15, and 30 min) FR or rest. Results MVC was reduced on subsequent days in the rest condition compared to FR (p = 0.002, p η 2 = 0.04); ROM was not different across time or condition (p = 0.193, p η 2 = 0.01). Stiffness characteristics of the VL were different on the third day of FR (p = 0.002, p η 2 = 0.03). RMS was statistically reduced 0, 15, and 30 min after FR compared to rest (p = 0.006, p η 2 = 0.03; p = 0.003, p η 2 = 0.04; p = 0.002, p η 2 = 0.04). Conclusions Following FR, MVC was elevated compared to rest and RMS was transiently reduced during a submaximal task. Excitation efficiency of the involved muscles may have been enhanced by FR, which protected against the decline in MVC which was observed with rest.

Abstract To investigate the interrelation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of patients with lung cancer in nine different ethnic groups. A retrospective review of the SEER database was conducted through the years 2007–2012. Population differences were assessed via chi‐square testing. Multivariable analyses (MVA) were used to detect overall survival (OS) differences in the total population (TP, N = 153,027) and for those patients presenting with Stage IV (N = 70,968). Compared to Whites, Blacks were more likely to present with younger age, male sex, lower income, no insurance, single/widowed partnership, less squamous cell carcinomas, and advanced stage; and experience less definitive surgery, lower OS, and lung cancer‐specific (LCSS) survival. White Hispanics presented with younger age, higher income, lower rates of insurance, single/widowed partnership status, advanced stage, more adenocarcinomas, and lower rates of definitive surgery, but no difference in OS and LCSS than Whites. In the TP and Stage IV populations, MVAs revealed that OS was better or equivalent to Whites for all other ethnic groups and was positively associated with insurance, marriage, and higher income. Blacks presented with more advanced disease and were more likely to succumb to lung cancer, but when adjusted for prognostic factors, they had a better OS in the TP compared to Whites. Disparities in income, marital status, and insurance rather than race affect OS of patients with lung cancer. Because of their presentation with advanced disease, Black and Hispanics are likely to have increased benefit from lung cancer screening.

The use of massive multiple-input multiple-output (MIMO) base stations in heterogeneous networks (HetNets) offers an increase in throughput without increasing the bandwidth, but with reduced power consumption. In this paper, we investigate the optimization problem of signal-to-interference-plusnoise ratio balancing for the case of imperfect channel state information at the transmitter. We present a fast converging robust beamforming solution for macrocell users in a typical HetNet scenario with massive MIMO at the base station. The proposed method applies the matrix stuffing technique and the alternative direction method of multipliers to give an efficient solution. Simulation results of a single-cell heterogeneous network show that the proposed solution yields performance with modest accuracy, while converging in an efficient manner, compared with optimal solutions achieved by the state-of-the-art modeling languages and interior-point solvers. This is particularly for cases when the number of antennas at the base station increases to large values. This makes the solution method attractive for practical implementation in heterogeneous networks with large-scale antenna arrays at the macrocell base station.

BackgroundLittle is understood regarding the inter-relation between economic, marital, and racial/ethnic differences in presentation and survival of surgically resected lung cancer patients. Our investigation will assess these differences in addition to known therapeutic, patient, and histopathologic factors.MethodsA retrospective review of the Surveillance Epidemiology and End Reporting database was conducted through the years 2007–2012. The population was split into nine different ethnic groups. Population differences were assessed via chi-square testing. Multivariable analysis (MVA) were used to detect overall survival (OS) differences in the total surgical population (TS, N = 35,689) in an ear (T1–T2

Background/Aim: In patients with advanced post-transplant hepatitis C virus (HCV) recurrence, antiviral treatment (AVT) with interferon and ribavirin is indicated to prevent graft failure. The aim of this study was to determine and report Canadian data with respect to the safety, efficacy, and spontaneous virologic response (SVR) predictors of AVT among transplanted patients with HCV recurrence. Patients and Methods: A retrospective chart review was performed on patients transplanted in London, Ontario and Edmonton, Alberta from 2002 to 2012 who were treated for HCV. Demographic, medical, and treatment information was collected and analyzed. Results: A total of 85 patients with HCV received pegylated interferon with ribavirin post-liver transplantation and 28 of the 65 patients (43%) with genotype 1 achieved SVR. Of the patients having genotype 1 HCV who achieved SVR, there was a significantly lower stage of fibrosis (1.37 ± 0.88 vs. 1.89 ± 0.96; P = 0.03), increased ribavirin dose (total daily dose 1057 ± 230 vs. 856 ± 399 mg; P = 0.02), increased rapid virologic response (RVR) (6/27 vs. 0/31; P = 0.05), increased early virologic response (EVR) (28/28 vs. 18/35; P = 0.006), and longer duration of therapy (54.7 ± 13.4 weeks vs. 40.2 ± 18.7; P = 0.001). A logistic regression model using gender, age, RVR, EVR, anemia, duration of therapy, viral load, years′ post-transplant, and type of organ (donation after cardiac death vs. donation after brain death) significantly predicted SVR (P < 0.001), with duration of therapy having a significant odds ratio of 1.078 (P = 0.007). Conclusions: This study identified factors that predict SVR in HCV-positive patients who received dual therapy post-transplantation. Extending therapy from 48 weeks to 72 weeks of dual therapy is associated with increased SVR rates. Future studies examining the role of extended therapy are needed to confirm these findings, since the current study is a retrospective one.

Background/Aims. Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that can progress to cirrhosis and hepatocellular carcinoma. This retrospective chart review investigated the incidence of hepatic steatosis in London, Ontario, Canada. Methods. A retrospective chart review was performed on emergency room (ER) patients undergoing nonscheduled computed tomography (CT) imaging over a six-month period in London, Ontario. CT images and reports were examined to determine presence of steatosis. Analyses of the electronic chart for a period of six months following the CT and communication with the patients’ family doctors were used to determine if there was follow-up. Waist circumference, subcutaneous fat depth, and abdominal fat volumes were calculated. Results. 48/450 patients meeting inclusion criteria were identified by radiology as having steatosis, with 34/40 (85%) family physicians unaware of the finding. 24.7% (100/405) of patients met standard CT criteria for steatosis, 40 of which were reported by the radiologist. Waist circumference, subcutaneous adipose tissue depth, subcutaneous adipose tissue volume, and visceral adipose tissue volume were significantly associated with steatosis. Conclusions. The hepatic steatosis prevalence we report is the first reported in a Canadian population. Early identification of steatosis will become more important as new pharmacologic therapies arise.

This paper reviews major research and development issues relating to hydrogels as scaffolds for tissue engineering, the article starts with a brief introduction of tissue engineering and hydrogels as extracellular matrix mimics, followed by a description of the various types of hydrogels and preparation methods, before a discussion of the physical and chemical properties that are important to their application. There follows a short comment on the trends of future research and development. Throughout the discussion there is an emphasis on the genetic understanding of bone tissue engineering application.

One general categorization of retinal ganglion cells is to segregate them into tonically or phasically responding neurons, each conveying discrete aspects of the visual scene. Although best identified in the output signals of the retina, this distinction is initiated at the first synapse: between photoreceptors and the dendrites of bipolar cells. In this study we found that the output synapses of bipolar cells also contribute to separate these pathways. Both transient and sustained ganglion cells can produce maintained spike activity, but bipolar cell glutamate release exhibits a divergence that corresponds to the response characteristics of the ganglion cells. Comparing light intensity coding in the sustained and transient ON pathways revealed that they shared the intensity spectrum. The transient pathway had greater sensitivity but smaller dynamic range, and switched from intensity coding to event detection at light levels where sustained pathway sensitivity began to rise. The distinctive properties of the sustained pathway depended upon inhibition and shifted toward those of the transient pathway in the absence of inhibition. The transient system was comparatively unaffected by the loss of inhibition and this was due to the concomitant activation of perisynaptic NMDA receptors. Overall, the properties of bipolar cell dendritic and axon terminals both contribute to the formation of key aspects of the sustained/transient dichotomy normally associated with ganglion cells.

Background: The National Lung Screening Trial demonstrated that screening for lung cancer improved overall survival (OS) and reduced lung cancer mortality in the 55-74-year-old age group by increasing the proportion of cancers detected at an early stage. Because of the increasing life expectancy of the American population, we investigated whether screening for lung cancer might benefit men and women aged 75-84 years. Materials/Methods: Rates of non-small cell lung cancer (NSCLC) from 2000-2009 were calculated in both these younger and older age groups using the Surveillance Epidemiology and End Reporting (SEER) database. OS and lung cancer -specific survival (LCSS) in patients with Stage I NSCLC diagnosed from 2004-2009 were analyzed to determine the effects of age and treatment. Results: The per capita incidence of NSCLC decreased in the 55-74 cohort, but increased in the 75-84 cohort over the study period. Crude lung cancer death rates in the two age groups who had no specific treatment were 39.5% and 44.9%, respectively. These rates fell in both age groups when increasingly aggressive treatment was used. Rates of OS and LCSS improved significantly with increasingly aggressive treatment in the 75-84 age group. The survival benefits of increasingly aggressive treatment in 75-84 year old females did not differ from their counterparts in the younger cohort. Conclusions: Screening for lung cancer might be of benefit to individuals at increased risk of lung cancer in the age 75-84 group. The survival benefits of aggressive therapy are similar in females between 55-74 and 75-84 years old.

Despite the prominent roles played by R2R3-MYB transcription factors in the regulation of plant gene expression, little is known about the details of how these proteins interact with their DNA targets. For example, while Arabidopsis thaliana R2R3-MYB protein AtMYB61 is known to alter transcript abundance of a specific set of target genes, little is known about the specific DNA sequences to which AtMYB61 binds. To address this gap in knowledge, DNA sequences bound by AtMYB61 were identified using cyclic amplification and selection of targets (CASTing). The DNA targets identified using this approach corresponded to AC elements, sequences enriched in adenosine and cytosine nucleotides. The preferred target sequence that bound with the greatest affinity to AtMYB61 recombinant protein was ACCTAC, the AC-I element. Mutational analyses based on the AC-I element showed that ACC nucleotides in the AC-I element served as the core recognition motif, critical for AtMYB61 binding. Molecular modelling predicted interactions between AtMYB61 amino acid residues and corresponding nucleotides in the DNA targets. The affinity between AtMYB61 and specific target DNA sequences did not correlate with AtMYB61-driven transcriptional activation with each of the target sequences. CASTing-selected motifs were found in the regulatory regions of genes previously shown to be regulated by AtMYB61. Taken together, these findings are consistent with the hypothesis that AtMYB61 regulates transcription from specific cis-acting AC elements in vivo. The results shed light on the specifics of DNA binding by an important family of plant-specific transcriptional regulators.

Tall cell carcinoma with reverse polarity is a rare subtype of breast carcinoma with solid and papillary growth and nuclear features reminiscent of those of the tall cell variant of papillary thyroid carcinoma. These tumors harbor recurrent IDH2 R172 hotspot mutations or TET2 mutations, co-occurring with mutations in PI3K pathway genes. Diagnosis of tall cell carcinomas with reverse polarity is challenging in view of their rarity and the range of differential diagnosis. We sought to determine the sensitivity and specificity of IDH2 R172 immunohistochemistry for the detection of IDH2 R172 hotspot mutations in this entity. We evaluated 14 tall cell carcinomas with reverse polarity (ten excision and five core needle biopsy specimens), 13 intraductal papillomas, 16 solid papillary carcinomas, and 5 encapsulated papillary carcinomas by Sanger sequencing of the IDH2 R172 hotspot locus and of exons 9 and 20 of PIK3CA, and by immunohistochemistry using monoclonal antibodies (11C8B1) to the IDH2 R172S mutation. The 14 tall cell carcinomas with reverse polarity studied harbored IDH2 R172 hotspot mutations, which co-occurred with PIK3CA hotspot mutations in 50% of cases. None of the other papillary neoplasms analyzed displayed IDH2 R172 mutations, however PIK3CA hotspot mutations were detected in 54% of intraductal papillomas, 6% of solid papillary carcinomas, and 20% of encapsulated papillary carcinomas tested. Immunohistochemical analysis with anti-IDH2 R172S antibodies (11C8B1) detected IDH2 R172 mutated protein in 93% (14/15) of tall cell carcinomas with reverse polarity samples including excision (n = 9/10) and core needle biopsy specimens (n = 5), whereas the remaining papillary neoplasms (n = 34) were negative. Our findings demonstrate that immunohistochemical analysis of IDH2 R172 is highly sensitive and specific for the detection of IDH2 R172 hotspot mutations, and likely suitable as a diagnostic tool in the evaluation of excision and core needle biopsy material of tall cell carcinomas with reverse polarity.