OPTN/SRTR 2011 Annual Data Report: lung.

Lungs are allocated in part based on the Lung Allocation Score (LAS), which considers risk of death without transplant and posttransplant. Wait-list additions have been increasing steadily after an initial decline following LAS implementation. In 2011, the largest number of adult candidates were added to the waiting list in a single year since 1998; donation and transplant rates have been unable to keep pace with wait-list additions. Candidates aged 65 years or older have been added faster than candidates in other age groups. After an initial decline following LAS implementation, wait-list mortality increased to 15.7 per 100 wait-list years in 2011. Short- and long-term graft survival improved in 2011; 10-year graft failure fell to an all-time low. Since 1998, the number of new pediatric (aged 0-11 years) candidates added yearly to the waiting list has declined. In 2011, 19 pediatric lung transplants were performed, a transplant rate of 34.7 per 100 wait-list years. The percentage of patients hospitalized before transplant has not changed. Both graft and patient survival have continued to improve over the past decade. Posttransplant complications for pediatric lung transplant recipients, similar to complications for adult recipients, include hypertension, renal dysfunction, diabetes, bronchiolitis obliterans syndrome, and malignancy.

Adjuvant Radiotherapy in Stage II Endometrial Cancer: Selective De-intensification of Adjuvant Treatment.

AIMS: Risk stratification, including nodal assessment, allows for selective de-intensification of adjuvant radiotherapy in stage II endometrial cancer. Patterns of treatment and clinical outcomes, including the use of reduced volume 'mini-pelvis' radiotherapy fields, were evaluated in a population-based study. MATERIALS AND METHODS: All patients diagnosed with pathological stage II endometrial cancer between 2000 and 2014, and received adjuvant radiotherapy in a regional healthcare jurisdiction were reviewed. Registry data were supplemented by a comprehensive review of patient demographics, disease characteristics and treatment details. The Charlson Comorbidity Score was calculated. Survival and recurrence data were analysed. RESULTS: In total, 264 patients met the inclusion criteria. Most patients had endometrioid histology (83%); 41% of patients had International Federation of Gynecologists and Obstetricians grade 1 disease. Half (49%) had surgical nodal evaluation; 11% received chemotherapy. Most patients (59%) were treated with full pelvic radiotherapy fields ± brachytherapy. Seventeen per cent of patients received mini-pelvis radiotherapy ± brachytherapy, whereas 24% received brachytherapy alone. Five-year recurrence-free survival was 87% for the entire cohort, with no significant difference by adjuvant radiotherapy approach. Only one patient receiving mini-pelvis radiotherapy ± brachytherapy recurred in the pelvis but outside of the mini-pelvis field. Recorded late toxicity rates were highest for full pelvis radiotherapy + brachytherapy. CONCLUSION: Risk stratification in a real-world setting allowed for selective de-intensification of adjuvant radiation with equivalent outcomes for stage II endometrial cancer. Mini-pelvis radiotherapy combined with brachytherapy is effective in highly selected patients, with the potential to decrease toxicity without compromising local control. Brachytherapy should be considered in low-risk stage II patients.

Lung and heart allocation in the United States.

Lung and heart allocation in the United States has evolved over the past 20-30 years to better serve transplant candidates and improve organ utilization. The current lung allocation policy, based on the Lung Allocation Score, attempts to take into account risk of death on the waiting list and chance of survival posttransplant. This policy is flexible and can be adjusted to improve the predictive ability of the score. Similarly, in response to the changing clinical phenotype of heart transplant candidates, heart allocation policies have evolved to a multitiered algorithm that attempts to prioritize organs to the most infirm, a designation that fluctuates with trends in therapy. The Organ Procurement and Transplantation Network and its committees have been responsive, as demonstrated by recent modifications to pediatric heart allocation and mechanical circulatory support policies and by ongoing efforts to ensure that heart allocation policies are equitable and current. Here we examine the development of US lung and heart allocation policy, evaluate the application of the current policy on clinical practice and explore future directions for lung and heart allocation.

Regulation of the expression of key genes involved in HDL metabolism by unsaturated fatty acids.

The cardioprotective effects of HDL have been largely attributed to their role in the reverse cholesterol transport pathway, whose efficiency is affected by many proteins involved in the formation and remodelling of HDL. The aim of the present study was to determine the effects, and possible mechanisms of action, of unsaturated fatty acids on the expression of genes involved in HDL metabolism in HepG2 cells. The mRNA concentration of target genes was assessed by real-time PCR. Protein concentrations were determined by Western blot or immunoassays. PPAR and liver X receptor (LXR) activities were assessed in transfection experiments. Compared with the SFA palmitic acid (PA), the PUFA arachidonic acid (AA), EPA and DHA significantly decreased apoA-I, ATP-binding cassette A1 (ABCA1), lecithin-cholesterol acyltransferase (LCAT) and phospholipid transfer protein mRNA levels. EPA and DHA significantly lowered the protein concentration of apoA-I and LCAT in the media, as well as the cellular ABCA1 protein content. In addition, DHA repressed the apoA-I promoter activity. AA lowered only the protein concentration of LCAT in the media. The activity of PPAR was increased by DHA, while the activity of LXR was lowered by both DHA and AA, relative to PA. The regulation of these transcription factors by PUFA may explain some of the PUFA effects on gene expression. The observed n-3 PUFA-mediated changes in gene expression are predicted to reduce the rate of HDL particle formation and maturation.

Does Loosening the Inclusion Criteria of the CROSS Trial Impact Outcomes in the Curative-Intent Trimodality Treatment of Oesophageal and Gastroesophageal Cancer Patients?

AIM: To determine the efficacy of preoperative chemoradiotherapy as per the CROSS protocol for oesophageal/gastroesophageal junction cancer (OEGEJC), when expanded to patients outside of the inclusion/exclusion criteria defined in the original clinical trial. MATERIALS AND METHODS: Data were collected retrospectively on 229 OEGEJC patients referred for curative-intent preoperative chemoradiotherapy. Outcomes including pathological complete response (pCR), overall survival (OS), cancer-specific survival and recurrence-free survival (RFS) of patients who met CROSS inclusion criteria (MIC) versus those who failed to meet criteria (FMIC) were determined. RESULTS: In total, 42.8% of patients MIC, whereas 57.2% FMIC; 16.6% of patients did not complete definitive surgery. The MIC cohort had higher rates of pCR, when compared with the FMIC cohort (33.3% versus 20.6%, P = 0.039). The MIC cohort had a better RFS, cancer-specific survival and OS compared with the FMIC cohort (P = 0.006, P = 0.004 and P = 0.009, respectively). Age >75 years and pretreatment weight loss >10% were not associated with a poorer RFS (P = 0.541 and 0.458, respectively). Compared with stage I-III patients, stage IVa was associated with a poorer RFS (hazard ratio (HR) = 2.158; 95% confidence interval (CI) = 1.339-3.480, P = 0.001). Tumours >8 cm in length or >5 cm in width had a trend towards worse RFS (HR = 2.060; 95% CI = 0.993-4.274, P = 0.052). CONCLUSION: Our study showed that the robust requirements of the CROSS trial may limit treatment for patients with potentially curable OEGEJC and can be adapted to include patients with a good performance status who are older than 75 years or have >10% pretreatment weight loss. However, the inclusion of patients with celiac nodal metastases or tumours >8 cm in length or >5 cm in width may be associated with poor outcomes.

Transcranial direct current stimulation's effect on novice versus experienced learning.

Transcranial direct current stimulation (TDCS) is a non-invasive form of brain stimulation applied via a weak electrical current passed between electrodes on the scalp. In recent studies, TDCS has been shown to improve learning when applied to the prefrontal cortex (e.g., Kincses et al. in Neuropsychologia 42:113-117, 2003; Clark et al. Neuroimage in 2010). The present study examined the effects of TDCS delivered at the beginning of training (novice) or after an hour of training (experienced) on participants' ability to detect cues indicative of covert threats. Participants completed two 1-h training sessions. During the first 30 min of each training session, either 0.1 mA or 2.0 mA of anodal TDCS was delivered to the participant. The anode was positioned near F8, and the cathode was placed on the upper left arm. Testing trials immediately followed training. Accuracy in classification of images containing and not-containing threat stimuli during the testing sessions indicated: (1) that mastery of threat detection significantly increased with training, (2) that anodal TDCS at 2 mA significantly enhanced learning, and (3) TDCS was significantly more effective in enhancing test performance when applied in novice learners than in experienced learners. The enhanced performance following training with TDCS persisted into the second session when TDCS was delivered early in training.

The role of allogeneic stem cell transplantation for adult acute lymphoblastic leukemia.

Acute lymphoblastic leukemia remains a challenging disease in adults. With modern multi-drug induction chemotherapy regimens, complete remission can be achieved in most patients. However, without additional therapy at the time of the first remission, most patients will eventually relapse. Regardless of the treatment option chosen at the time of relapse, outcomes after relapse are poor, with only around 10% of all patients surviving after relapse. Thus, decision-making at the time of achieving the first complete remission is critical. Allogeneic stem cell transplantation is highly effective at preventing relapse, but with significant treatment related toxicity. Ongoing chemotherapy in the form of consolidation and maintenance may be less effective at preventing relapse, but with lower toxicities. Thus, the superiority of allogeneic stem cell transplantation must be balanced against the lower toxicity of consolidation chemotherapy. This decision is further complicated by rapid changes in the field of hematopoietic stem cell transplantation, such as the use of reduced intensity conditioning regimens and alternative stem cell sources such as cord blood transplants. The available evidence suggests that allogeneic transplantation is a viable treatment option for patients in first complete remission, with overall survival superior to traditional consolidation and maintenance chemotherapy. However, whether transplantation based post-remission therapy is superior to modern, pediatric-based non-transplant chemotherapy regimens remains unclear.

A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis.

Epilepsy is a complex neurological condition characterized by repeated spontaneous seizures and can be induced by initiating seizures known as status epilepticus (SE). Elaborating the critical molecular mechanisms following SE are central to understanding the establishment of chronic seizures. Here, we identify a transient program of molecular and metabolic signaling in the early epileptogenic period, centered on day five following SE in the pre-clinical kainate or pilocarpine models of temporal lobe epilepsy. Our work now elaborates a new molecular mechanism centered around Wnt signaling and a growing network comprised of metabolic reprogramming and mTOR activation. Biochemical, metabolomic, confocal microscopy and mouse genetics experiments all demonstrate coordinated activation of Wnt signaling, predominantly in neurons, and the ensuing induction of an overall aerobic glycolysis (Warburg-like phenomenon) and an altered TCA cycle in early epileptogenesis. A centerpiece of the mechanism is the regulation of pyruvate dehydrogenase (PDH) through its kinase and Wnt target genes PDK4. Intriguingly, PDH is a central gene in certain genetic epilepsies, underscoring the relevance of our elaborated mechanisms. While sharing some features with cancers, the Warburg-like metabolism in early epileptogenesis is uniquely split between neurons and astrocytes to achieve an overall novel metabolic reprogramming. This split Warburg metabolic reprogramming triggers an inhibition of AMPK and subsequent activation of mTOR, which is a signature event of epileptogenesis. Interrogation of the mechanism with the metabolic inhibitor 2-deoxyglucose surprisingly demonstrated that Wnt signaling and the resulting metabolic reprogramming lies upstream of mTOR activation in epileptogenesis. To augment the pre-clinical pilocarpine and kainate models, aspects of the proposed mechanisms were also investigated and correlated in a genetic model of constitutive Wnt signaling (deletion of the transcriptional repressor and Wnt pathway inhibitor HBP1). The results from the HBP1-/- mice provide a genetic evidence that Wnt signaling may set the threshold of acquired seizure susceptibility with a similar molecular framework. Using biochemistry and genetics, this paper outlines a new molecular framework of early epileptogenesis and advances a potential molecular platform for refining therapeutic strategies in attenuating recurrent seizures.

Acquisition of antigens characteristic of adult pericentral hepatocytes by differentiating fetal hepatoblasts in vitro.

Antigens specific to pericentral hepatocytes have been studied in adult mouse liver, during fetal development, and in cultured fetal hepatoblasts. Antibody reactive with glutamine synthetase stained all fetal liver cells but almost all cells lost this antigen after birth; only a single layer of pericentral cells retained it in adulthood. In contrast, monoclonal antibodies to major urinary protein (MUP) did not detect the antigen until approximately 3 wk after birth, after which time the cells within 6-10 cell diameters of the central veins were positive. Cultured fetal liver cells from embryos at 13 +/- 1 d of gestation were capable of differentiating in vitro to mimic events that would occur had the cells remained in the animal. About 10-20% of the explanted cells grew into clusters of hepatocyte-like cells, all of which stained with albumin antibodies. MUP monoclonals were reactive with one-half of the differentiated fetal hepatocytes. Glutamine synthetase was present in all hepatocytes after several days in culture and gradually decreased and remained in only occasional cells, all of which also contained the MUP antigen. These findings suggest that a sequence of gene controls characterizes expression of specific genes in developing liver, and that differentiating fetal hepatoblasts are capable of undergoing similar patterns of gene activity in culture.

The HBP1 transcriptional repressor participates in RAS-induced premature senescence.

Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Previous work shows that RAS and p38 MAPK participate in premature senescence, but transcriptional effectors have not been identified. Here, we demonstrate that the HBP1 transcriptional repressor participates in RAS- and p38 MAPK-induced premature senescence. In cell lines, we had previously isolated HBP1 as a retinoblastoma (RB) target but have determined that it functions as a proliferation regulator by inhibiting oncogenic pathways as a transcriptional repressor. In primary cells, the results indicate that HBP1 is a necessary component of premature senescence by RAS and p38 MAPK. Similarly, a knockdown of WIP1 (a p38 MAPK phosphatase) induced premature senescence that also required HBP1. Furthermore, HBP1 requires regulation by RB, in which few transcriptional regulators for premature senescence have been shown. Together, the data suggest a model in which RAS and p38 MAPK signaling engage HBP1 and RB to trigger premature senescence. As an initial step toward clinical relevance, a bioinformatics approach shows that the relative expression levels of HBP1 and WIP1 correlated with decreased relapse-free survival in breast cancer patients. Together, these studies highlight p38 MAPK, HBP1, and RB as important components for a premature-senescence pathway with possible clinical relevance to breast cancer.

Alterations of the HBP1 transcriptional repressor are associated with invasive breast cancer.

Invasive breast cancer has a high risk of recurrence to incurable disease and needs improved prognostic and therapeutic tools. Our work combines clinical and molecular analyses to show that the transcriptional repressor HBP1 may be a new target for invasive breast cancer. Previous work indicated that HBP1 regulated proliferation and senescence and inhibited Wnt signaling. Two of these functions have been associated with invasive breast cancer. In 76 breast tumors, we identified 10 HBP1 mutations/variants that were associated with fully invasive breast cancer. In a separate analysis, we found that a subset of invasive breast cancer specimens also had reduced HBP1 mRNA levels. These clinical correlations suggested that mutation or reduction of HBP1 occurs in invasive breast cancer and that HBP1 might regulate the proliferation and invasiveness of this breast cancer type. Analysis of the HBP1 mutants showed they were functionally defective for suppressing Wnt signaling. To test the consequences of reduced HBP1 levels, we used RNA interference to knock down HBP1 and observed increased Wnt signaling, tumorigenic proliferation, and invasiveness in cell and animal breast cancer models. Lastly, statistical analysis of a breast cancer patient database linked reduced HBP1 expression to breast cancer recurrence. In considering two-gene criteria for relapse potential, reduced expression of HBP1 and SFRP1, which is another Wnt inhibitor that was recently linked to invasive breast cancer, strikingly correlated with recurrence. Together, these data indicate that HBP1 may be a molecularly and clinically relevant regulator of breast cancer transitions that eventually lead to poor prognosis.

Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA.

Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.

Novel tyrosine kinase identified by phosphotyrosine antibody screening of cDNA libraries.

In an attempt to clone protein tyrosine kinases, antiphosphotyrosine antibodies were used to screen lambda gt11 cDNA expression libraries. By this method, a 2.5-kilobase cDNA encoding a novel tyrosine kinase was isolated from a mouse liver cDNA library. This new gene is most closely related to the receptor tyrosine kinases ret, fms, and kit.

Positional and developmental regulation of glutamine synthetase expression in mouse liver.

In situ hybridization showed that all fetal hepatocytes contain glutamine synthetase (GS) mRNA but that in adult mouse liver, only a single cell layer surrounding the central veins contains GS mRNA. A shift from the fetal to the adult pattern begins within a few days of birth and is complete within 12 days of birth. Since the total GS mRNA and the transcription rate of the single GS gene are similar at birth and in adults, we conclude that there is a generalized reduction in GS transcription for most hepatocytes and a sharp rise in GS transcription for the immediate pericentral cells. This may be a case of positional regulation of specific gene transcription in apparently a single cell lineage.

Analysis of the upstream elements of the xenobiotic compound-inducible and positionally regulated glutathione S-transferase Ya gene.

In situ hybridization and other data showed that all hepatocytes express glutathione-S-transferase (GST) Ya mRNA but that specifically pericentral cells can be induced 15- to 20-fold with 3-methylcholanthrene (3-MC). In order to identify DNA sequences involved in inducible expression (pericentral hepatocytes) and constitutive expression (all hepatocytes), the upstream regions of the GST Ya gene were further analyzed by transient transfection and DNA-binding studies to identify the nature of proteins involved in regulating this gene. The sequences from -980 to -650 were necessary and sufficient for cell-specific and inducible expression. Within this enhancer region, four nuclear protein-binding sites were identified. One site required for inducible expression was bound by a protein(s) induced by 3-MC. Two other sites were bound by proteins similar or identical to the constitutive hepatocyte nuclear factors HNF1 and HNF4. The fourth site was shown to be bound by a non-liver-specific nuclear protein that is also important in the function of the albumin gene enhancer.

HBP1 repression of the p47phox gene: cell cycle regulation via the NADPH oxidase.

Several studies have linked the production of reactive oxygen species (ROS) by the NADPH oxidase to cellular growth control. In many cases, activation of the NADPH oxidase and subsequent ROS generation is required for growth factor signaling and mitogenesis in nonimmune cells. In this study, we demonstrate that the transcriptional repressor HBP1 (HMG box-containing protein 1) regulates the gene for the p47phox regulatory subunit of the NADPH oxidase. HBP1 represses growth regulatory genes (e.g., N-Myc, c-Myc, and cyclin D1) and is an inhibitor of G(1) progression. The promoter of the p47phox gene contains six tandem high-affinity HBP1 DNA-binding elements at positions -1243 to -1318 bp from the transcriptional start site which were required for repression. Furthermore, HBP1 repressed the expression of the endogenous p47phox gene through sequence-specific binding. With HBP1 expression and the subsequent reduction in p47phox gene expression, intracellular superoxide production was correspondingly reduced. Using both the wild type and a dominant-negative mutant of HBP1, we demonstrated that the repression of superoxide production through the NADPH oxidase contributed to the observed cell cycle inhibition by HBP1. Together, these results indicate that HBP1 may contribute to the regulation of NADPH oxidase-dependent superoxide production through transcriptional repression of the p47phox gene. This study defines a transcriptional mechanism for regulating intracellular ROS levels and has implications in cell cycle regulation.

Dioxin receptor and C/EBP regulate the function of the glutathione S-transferase Ya gene xenobiotic response element.

The rat glutathione S-transferase Ya gene xenobiotic response element (XRE) has both constitutive and xenobiotic-inducible activity. We present evidence that the XRE is regulated by both the constitutive C/EBP transcription factor and the xenobiotic-activated dioxin receptor. A ligand-activated XRE-binding protein was shown to be dioxin receptor by specific antibody immunodepletion and binding of highly purified receptor. Identification of C/EBP alpha as the constitutive binding protein was demonstrated by competition with a C/EBP binding site, protein-DNA cross-linking to determine the molecular weight of the constitutive protein(s), specific antibody immunodepletion, and binding of purified bacterially expressed C/EBP alpha. Mutational analysis of the XRE revealed that the constitutive factor (C/EBP alpha) shares a nearly identical overlapping binding site with the dioxin receptor. In functional testing of the putative C/EBP-XRE interaction, cotransfected C/EBP alpha activated an XRE test promoter in the non-xenobiotic-responsive HeLa cell line. Unexpectedly, cotransfected C/EBP alpha had no effect on basal activity but significantly increased the xenobiotic response of the XRE test promoter in the xenobiotic-responsive, C/EBP-positive HepG2 cell line. Furthermore, inhibition of C/EBP-binding protein(s) in HepG2 cells by transfection of C/EBP oligonucleotides suppressed the xenobiotic response. These results suggest that C/EBP alpha and dioxin receptor recognize the same DNA sequence element and that transcriptional regulation can occur by cooperative interactions between these two transcription factors.

The transcriptional repressor HBP1 is a target of the p38 mitogen-activated protein kinase pathway in cell cycle regulation.

The p38 mitogen-activated protein (MAP) kinase signaling pathway participates in both apoptosis and G1 arrest. In contrast to the established role in apoptosis, the documented induction of G1 arrest by activation of the p38 MAP kinase pathway has attracted recent attention with reports of substrates that are linked to cell cycle regulation. Here, we identify the high-mobility group box protein HBP1 transcriptional repressor as a new substrate for p38 MAP kinase. Our previous work had shown that HBP1 inhibits G1 progression in cell and animal models, and thus indicated that HBP1 could be a relevant substrate for p38 MAP kinase in cell cycle regulation. In the present work, a p38 MAP kinase docking site (amino acids [aa] 81 to 125) and a p38 MAP kinase phosphorylation site (serine 401) were identified in the HBP1 protein. Furthermore, the docking and phosphorylation sites on HBP1 were specific for p38 MAP kinase. In defining the role of p38 MAP kinase regulation, the inhibition of p38 MAP kinase activity was shown to decrease HBP1 protein levels by triggering protein instability, as manifested by a decrease in protein half-life. Consistently, a decrease in protein levels was accompanied by a decrease in overall DNA binding activity. A mutation of the p38 MAP kinase phosphorylation site at aa 401 [(S-A)401HBP1] also triggered HBP1 protein instability. While protein stability was compromised by mutation, the specific activities of (S-A)401HBP1 and of wild-type HBP1 appeared comparable for transcriptional repression. This comparison of transcription-specific activity highlighted that p38 MAP kinase regulated HBP1 protein levels but not the intrinsic activity for DNA binding or for transcriptional repression. Finally, p38 MAP kinase-mediated regulation of the HBP1 protein also contributed to the regulation of G1 progression. Together, our work supports a molecular framework in which p38 MAP kinase activity contributes to cell cycle inhibition by increasing HBP1 and other G1 inhibitory factors by regulating protein stability.

HMG box transcriptional repressor HBP1 maintains a proliferation barrier in differentiated liver tissue.

We previously isolated HBP1 as a target of the retinoblastoma (RB) and p130 family members and as the first of the HMG box transcriptional repressors. Our subsequent work demonstrated that HBP1 coordinates differentiation in cell culture models. In the present study, we show that HBP1 regulates proliferation in a differentiated tissue of an animal. Using transgenic mice in which HBP1 expression was specifically increased in hepatocytes under control of the transthyretin promoter, we determined the impact of HBP1 on synchronous cell cycle reentry following partial hepatectomy. Modest overexpression of HBP1 yielded a detectable cell cycle phenotype. Following a mitogenic stimulus induced by two-thirds partial hepatectomy, mice expressing the HBP1 transgene showed a 10- to 12-h delay in progression through G(1) to the peak of S phase. There was a concomitant delay in mid-G(1) events, such as the induction of cyclin E. While the delay in G(1) and S phases correlated with the slight overexpression of transgenic HBP1, the level of the endogenous HBP1 protein itself declined in S phase. In contrast, the onset of the immediate-early response following partial hepatectomy was unchanged in HBP1 transgenic mice. This observation indicated that the observed delay in S phase did not result from changes in signaling pathways leading into the G(0)-to-G(1) transition. Finally, transgenic mice expressing a mutant HBP1 lacking the N-terminal RB interacting domain showed a stronger S-phase response following partial hepatectomy. These results provide the first evidence that HBP1 can regulate cell cycle progression in differentiated tissues.

Radiotherapy in the Multidisciplinary Management of Adenomyoepithelioma of the Breast with an Axillary Lymph Node Metastasis: A Case Report and Review of the Literature.

We describe a case of aggressive adenomyoepithelioma (AME) of the breast with a lymph node metastasis. A 63-year-old female presented with a fluctuating breast mass and clinically palpable lymph nodes. The patient underwent excisional biopsy followed by mastectomy with lymph node dissection and adjuvant radiotherapy (RT). Clinical behavior of both benign and malignant AME is described with the review of the literature and treatment recommendations.