Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures.

Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including 18F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution

N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA

BACKGROUND: Cellular senescence is a state in which mammalian cells enter into an irreversible growth arrest and altered biological functions. The senescence response in mammalian cells can be elicited by DNA-damaging agents. In the present study we report that the DNA-damaging agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is able to induce senescence in the HCT-116 colon cancer cell line. RESULTS: Cells treated with lower concentrations of MNNG (0–25 microM) for 50 h showed a dose-dependent increase in G(2)/M phase arrest and apoptosis; however, cells treated with higher concentrations of MNNG (50–100 microM) showed a senescence-like G(0)/G(1 )phase arrest which was confirmed by increased expression of β-galactosidase, a senescence induced marker. The G(2/)M phase arrest and apoptosis were found to be associated with increased levels of p53 protein, but the senescence-like G(0)/G(1 )phase arrest was dissociated with p53 protein levels, since the p53 protein levels decreased in senescence-like arrested cells. We further, determined whether the decreased level of p53 was a transcriptional or a translational phenomenon. The results revealed that the decreased level of p53 protein in senescence-like arrested cells was a transcriptional phenomenon since p53 mRNA levels simultaneously decreased after treatment with higher concentrations of MNNG. We also examined the effect of MNNG treatment on other cell cycle-related proteins such as p21, p27, cyclin B1, Cdc2, c-Myc and max. The expression levels of these proteins were increased in cells treated with lower concentrations of MNNG, which supported the G(2)/M phase arrest. However, cells treated with higher concentrations of MNNG showed decreased levels of these proteins, and hence, may not play a role in cell cycle arrest. We then examined a possible association of the expression of APC protein and telomeric DNA signals with cellular senescence in MNNG-treated cells. We found that protein and mRNA levels of APC were drastically reduced in cells treated with higher concentrations of MNNG. The loss of APC expression might lead to chromosomal instability as well as microtubular disorganization through its dissociation with tubulin. In fact, the protein level of α-tubulin was also drastically decreased in senescence-like arrested cells treated with higher concentrations of MNNG. The levels of telomeric DNA also decreased in cells treated with higher concentrations of MNNG. CONCLUSIONS: These results suggest that in response to DNA alkylation damage the senescence-like arrest of HCT-116 cells was associated with decreased levels of APC protein, microtubular organization, and telomeric DNA

A rare pediatric renal tumor: classic congenital mesoblastic nephroma: two cases and review of literature

Background Mesoblastic nephroma (Boland’s tumor) is the most common benign renal tumor occurring in infants and neonates. The most common presentation is abdominal mass, but it can have varied presentations because of associated paraneoplastic syndromes. Majority of these tumors can be cured with surgical excision alone; however, long-term follow-up is required for recurrence or metastasis. Histopathologically, it is divided into two subtypes: classic and cellular. The less common cellular congenital mesoblastic nephromas have cellular elements in them and tend to have a more malignant potential.Patients and methods Two patients were studied over a period of 2 years from June 2010 to June 2012.Results By reporting two patients presenting in the infantile period with classic congenital mesoblastic nephromas, an attempt is made in this paper to characterize the clinical behavior of this variety of renal tumors. Hypertension and paraneoplastic syndromes can be associated with this tumor. Herein we compare our experience with other similar cases reported in the literature.Conclusion When renal tumors occur in infancy or at neonatal age, mesoblastic nephroma should be kept in mind. Association of hypertension and paraneoplastic syndromes should be looked for. Surgery is usually curative and postoperative follow-up for recurrence is required, more so in cellular variety

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk

Quantum limits of superconducting-photonic links and their extension to mm-waves

Photonic addressing of superconducting circuits has been proposed to overcome wiring complexity and heat load challenges, but superconducting-photonic links suffer from an efficiency-noise trade-off that limits scalability. This trade-off arises because increasing power conversion efficiency requires reducing optical power, which makes the converted signal susceptible to shot noise. We analyze this trade-off and find the infidelity of qubit gates driven by photonic signals scales inversely with the number of photons used, and therefore the power efficiency of the converter. While methods like nonlinear detection or squeezed light could mitigate this effect, we consider generating higher frequency electrical signals, such as millimeter-waves (100 GHz), using laser light. At these higher frequencies, circuits have higher operating temperatures and cooling power budgets. We demonstrate an optically-driven cryogenic millimeter-wave source with a power efficiency of $10^{-4}$ that can generate ${1}~\mathrm{\mu W}$ of RF power at 80 GHz with 1500 thermal photons of added noise at 4 K. Using this source, we perform frequency-domain spectroscopy of superconducting NbTiN resonators at 80-90 GHz. Our results show a promising approach to alleviate the efficiency-noise constraints on optically-driven superconducting circuits while leveraging the benefits of photonic signal delivery. Further optimization of power efficiency and noise at high frequencies could make photonic control of superconducting qubits viable at temperatures exceeding 1 kelvin.Comment: 14 pages, 8 figure

Hepaticoduodenostomy as a technique for biliary anastomosis in children with choledochal cyst: An experience with 31 cases

Objective The aim of this study was to investigate the efficacy and complications of hepaticoduodenostomy in the treatment of choledochal cyst in children. Summary background data The conventional treatment of choledochal cyst includes Roux-en-Y hepaticojejunostomy for biliary reconstruction. This procedure, however, disrupts normal bowel continuity and requires two anastomoses. We studied the technique of hepaticoduodenostomy as an effective alternative to this technique.Patients and methods A total of 31 children undergoing  hepatoduodenostomy for choledochal cyst over a period of 9 years were included in this study.Results The patients operated upon had outcomes similar to those treated by the Roux-en-Y technique in other studies.Conclusion Hepaticoduodenostomy is an effective alternative to the conventional Roux-en-Y anastomotic technique in cases of choledochal cyst in children. Keywords: choledochal cyst, hepaticoduodenostomy, pediatri

Increasing Efforts to Reduce Cervical Cancer through State-Level Comprehensive Cancer Control Planning

Reducing cervical cancer disparities in the U.S. requires intentional focus on structural barriers such as systems and policy which impact access to human papillomavirus (HPV) vaccination, cervical cancer screening and treatment. Such changes are difficult and often politicized. State comprehensive cancer control (CCC) plans are vehicles that, if designed well, can help build collective focus on structural changes. Study objectives were to identify the prioritization of cervical cancer in state CCC plans, the conceptualization of HPV within these plans, and the focus of plans on structural changes to reduce cervical cancer disparities. Data were gathered by systematic content analysis of CCC plans from 50 states and the District of Columbia from February-June 2014 for evidence of cervical cancer prioritization, conceptualization of HPV, and focus on structural barriers to cervical cancer vaccination, screening or treatment. Findings indicate that prioritization of cervical cancer within state CCC plans may not be a strong indicator of state efforts to reduce screening and treatment disparities. While a majority of plans reflected scientific evidence that HPV causes cervical and other cancers, they did not focus on structural elements impacting access to evidence-based interventions. Opportunities exist to improve state CCC plans by increasing their focus on structural interventions that impact cervical cancer prevention, detection, and treatmentparticularly for the 41% of plans ending in 2015 and the 31% ending between 2016-2020. Future studies should focus on the use of policy tools in state CCC plans and their application to cervical cancer prevention and treatment

The maize brown midrib6 (bm6) mutation encodes a functional GTP Cyclohydrolase1

Brown midrib mutations in maize (Zea mays L.) and sorghum (Sorghum bicolor L.) alter lignin composition and enhance cell wall digestibility. These mutations are prime candidates for silage breeding. Six brown midrib mutants are currently known, brown midrib1 (bm1) to brown midrib6 (bm6). The bm1 and bm3 mutations are being used commercially for silage. The underlying genes responsible for five of the six bm mutations in maize (bm1, bm2, bm3, bm4, and bm5) are known. Chen and co-workers (2012) characterized the bm6 mutation, demonstratingthat bm6 increases cell wall digestibility and physically mapped bm6 within a 180 kilobase region on chromosome 2. The present investigation utilized map-based cloning to identify the candidate gene responsible for the bm6 phenotype as GTP Cyclohydrolase1 (GCH1) and validated the candidate gene through reverse genetics. Orthologs of bm6 include at least one paralogous gene in maize on chromosome 10 and various homologs in other grasses and dicots. The discovery that GCH1 is  responsible for the maize bm6 phenotype suggests that GCH1 plays a role in the tetrahydrofolate biosynthetic process

Vermont Immigrant Health Insurance Plan: Outreach and Education

Background On July 1, 2022, Vermont legislature enacted the Immigrant Health Insurance Plan (IHIP) designed to provide health insurance for pregnant people and children under the age of 19 who do not qualify for Medicaid due to immigration status. While many have enrolled, we aim to assess whether current outreach and educational materials effectively prepare healthcare professionals, advocates, and community organizations identify and enroll eligible individuals. Methods We developed an electronic survey compromised of 13 close-ended questions and 6 open-ended questions. The survey was distributed statewide to primary care providers, social workers, community partners, and the Department of Vermont Health Access (DVHA) Assisters. Key themes from the open-ended questions were identified and examined. Interviews with key community partners, Vermont Representative Houghton, the University of Vermont Medical Center Financial Advocacy group, DVHA and the Health Care Advocates at Vermont Legal Aid helped inform our perspective and contributed to the development of the survey questions. Results We received 125 responses, with the majority (57%) being medical providers. A considerable number of respondents (64.8%) reported being unfamiliar with the IHIP program. When looking specifically at medical providers, this percentage rose to 88.4%. We found that individuals had similar levels of unfamiliarity with IHIP statewide. Importantly, only 4.6% of total respondents believed there was adequate knowledge of IHIP amongst the eligible population. Conclusions There is a pressing need for increased awareness and education of IHIP amongst healthcare professionals that work directly with immigrants. A widespread effort throughout Vermont is needed, as respondents from counties outside of Chittenden County, Vermont’s most populous county, demonstrate similar levels of unfamiliarity as within it. To increase awareness, respondents provided suggestions for multi-lingual education efforts, such as brochures, informative sessions, and trainings. We plan to collaborate with AHEC to develop educational opportunities for the primary care workforce