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Discusses the abstract of the study 'Satisfaction With and Outcome of Risk Reducing Surgeries Among a Series of BRCA Heterozygotes,' presented at the 21st Annual Education Conference of the National Society of Genetic Counselors held in Phoenix, Arizona in November 2002.

Twenty-four patients with blastic-phase chronic myelogenous leukemia (CML) were treated with mitoxantrone. The patients included 19 whose cells were Philadelphia chromosome (Ph1+) and 5 who were either Ph1- or in whom cytogenetics were not available. Six of the 19 whose cells were Ph1+ responded and one of those who were Ph1- responded. The patients were further characterized into lymphoid or nonlymphoid on the basis of terminal deoxynucleotidyl transferase or morphology. Two of the patients with lymphoid transformation and 3 of those with nonlymphoid transformation responded. In 3 patients post-treatment cytogenetic evaluation revealed the presence of Ph1- metaphases. We conclude that mitoxantrone has modest activity in blCML and that the cytogenetic responses suggest the possibility of greater efficacy in chronic-phase CML. [ABSTRACT FROM AUTHOR]

During limb bud formation, axis polarities are established as evidenced by the spatially restricted expression of key regulator genes. In particular, the mutually antagonistic interaction between the GLI3 repressor and HAND2 results in distinct and non-overlapping anterior-distal Gli3 and posterior Hand2 expression domains. This is a hallmark of the establishment of antero-posterior limb axis polarity, together with spatially restricted expression of homeodomain and other transcriptional regulators. Here, we show that TBX3 is required for establishment of the posterior expression boundary of anterior genes in mouse limb buds. ChIP-seq and differential gene expression analysis of wild-type and mutant limb buds identifies TBX3-specific and shared TBX3-HAND2 target genes. High sensitivity fluorescent whole-mount in situ hybridisation shows that the posterior expression boundaries of anterior genes are positioned by TBX3-mediated repression, which excludes anterior genes such as Gli3, Alx4, Hand1 and Irx3/5 from the posterior limb bud mesenchyme. This exclusion delineates the posterior mesenchymal territory competent to establish the Shh-expressing limb bud organiser. In turn, HAND2 is required for Shh activation and cooperates with TBX3 to upregulate shared posterior identity target genes in early limb buds., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Arousal to ejaculation latency time interval (AETI) and erection to ejaculation latency time interval (EETI) are new tools used to measure ejaculatory latency time (ET). Unlike intravaginal ejaculation latency time (IELT), they are applicable for sexual activities other than penovaginal intercourse and do not require penetration. We assessed the distribution and relation between AETI, EETI, and IELT in Indian men., Methods: Voluntary participation was sought to recruit subjects reporting premature ejaculation (PE) and normal ejaculation. Those able to record the ETs correctly were then asked to record their ETs for two subsequent sexual events., Results: A total of 26 subjects (13 - normal and 13 - PE) were able to complete the study. The mean age of the participants was 29.85 ± 4.8 years, with no difference seen between the two groups. The mean AETI, EETI, and IELT were 817 ± 592.016 s, 726 ± 566.346 s, and 582 ± 450.859 s, respectively, in normal subjects. PE subjects had significantly lesser mean ETs, AETI 80.62 ± 24.74 s, EETI 53.46 ± 25.441 s, and IELT 21 ± 14.785 s. Regression analysis found that 131.67 s of AETI and 99.58 s of EETI were equivalent to 60 s of IELT., Conclusions: AETI and EETI have positively skewed distribution similar to IELT. Premature ejaculators had less difference between AETI and EETI, suggesting that sexual cycle gets completed immediately following arousal in these subjects causing PE., Competing Interests: Conflicts of Interest: There are no conflicts of interest., (Copyright: © 2021 Indian Journal of Urology.)

Chromatin remodeling and genomic alterations impact spatio-temporal regulation of gene expression, which is central to embryonic development. The analysis of mouse and chicken limb development provides important insights into the morphoregulatory mechanisms, however little is known about the regulatory differences underlying their morphological divergence. Here, we identify the underlying shared and species-specific epigenomic and genomic variations. In mouse forelimb buds, we observe striking synchrony between the temporal dynamics of chromatin accessibility and gene expression, while their divergence in chicken wing buds uncovers species-specific regulatory heterochrony. In silico mapping of transcription factor binding sites and computational footprinting establishes the developmental time-restricted transcription factor-DNA interactions. Finally, the construction of target gene networks for HAND2 and GLI3 transcriptional regulators reveals both conserved and species-specific interactions. Our analysis reveals the impact of genome evolution on the regulatory interactions orchestrating vertebrate limb bud morphogenesis and provides a molecular framework for comparative Evo-Devo studies., (© 2021. The Author(s).)

Precise cis-regulatory control of gene expression is essential for normal embryogenesis and tissue development. The BMP antagonist Gremlin1 (Grem1) is a key node in the signalling system that coordinately controls limb bud development. Here, we use mouse reverse genetics to identify the enhancers in the Grem1 genomic landscape and the underlying cis-regulatory logics that orchestrate the spatio-temporal Grem1 expression dynamics during limb bud development. We establish that transcript levels are controlled in an additive manner while spatial regulation requires synergistic interactions among multiple enhancers. Disrupting these interactions shows that altered spatial regulation rather than reduced Grem1 transcript levels prefigures digit fusions and loss. Two of the enhancers are evolutionary ancient and highly conserved from basal fishes to mammals. Analysing these enhancers from different species reveal the substantial spatial plasticity in Grem1 regulation in tetrapods and basal fishes, which provides insights into the fin-to-limb transition and evolutionary diversification of pentadactyl limbs., (© 2021. The Author(s).)

Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Various kinds of stressors and psychological problems have been reported in the adolescent student population. This study assessed and compared depression, anxiety, and various coping styles among high school students attending coaching classes for medical entrance examination (MEE) and those not., Materials and Methods: Systemic random sampling technique was used to recruit 400 high school students with equal number of those attending (Group 1) and those not attending any coaching class for MEE (Group 2). They underwent screening for depression and anxiety through Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item. Coping styles were assessed through brief COPE inventory. Screening positive subjects were assessed in detail by a psychiatrist using ICD-10 (International Classification of Diseases 10 th Revision), Diagnostic Criteria for Research (DCR). The severity of depression and anxiety was measured through HAM-D and HAM-A, respectively., Results: Depression and anxiety were reported by higher proportion of Group 1 (36%) than Group 2 (22%), χ 2 (1) = 9.52; P = 0.002. In both the groups, depressive disorder was the most common, followed by generalised anxiety-disorder and mixed anxiety-depression. The severity of depression (HAM-D score) and anxiety (HAM-A Score) was significantly more Group 1. "Active coping" ( χ 2 = 4.79 P = 0.02) and "Humor" ( χ 2 = 30.90, P ≤ 0.01) were more commonly used by healthy students, while "Religious coping" ( χ 2 = 37.92 P ≤ 0.01) were the most common among those diagnosed with depression/anxiety disorder., Conclusion: Higher prevalence of the psychological problems in adolescent school students preparing for MEE highlights the importance of aptitude assessment, career counseling, and school mental health program before their exposure to the competitive academic atmosphere., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Education and Health Promotion.)

In early development, the environment triggers mnemonic epigenomic programs resulting in memory and learning experiences to confer cognitive phenotypes into adulthood. To uncover how environmental stimulation impacts the epigenome and genome organization, we used the paradigm of environmental enrichment (EE) in young mice constantly receiving novel stimulation. We profiled epigenome and chromatin architecture in whole cortex and sorted neurons by deep-sequencing techniques. Specifically, we studied chromatin accessibility, gene and protein regulation, and 3D genome conformation, combined with predicted enhancer and chromatin interactions. We identified increased chromatin accessibility, transcription factor binding including CTCF-mediated insulation, differential occupancy of H3K36me3 and H3K79me2, and changes in transcriptional programs required for neuronal development. EE stimuli led to local genome re-organization by inducing increased contacts between chromosomes 7 and 17 ( inter- chromosomal). Our findings support the notion that EE-induced learning and memory processes are directly associated with the epigenome and genome organization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Espeso-Gil, Holik, Bonnin, Jhanwar, Chandrasekaran, Pique-Regi, Albaigès-Ràfols, Maher, Permanyer, Irimia, Friedländer, Pons-Espinal, Akbarian, Dierssen, Maass, Hor and Ossowski.)

Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Cognitive screening in elderly patients receiving treatment for chronic medical conditions in a busy outpatient clinical setting is crucial to detect dementia at an earlier stage. Although Hindi Mini-Mental State Examination (HMSE) is an established screening tool for the geriatric population in India, but cannot be administered with the informant. Our study aims to compare two screening instruments, Informant based - Eight-item Interview to Differentiate Aging and Dementia (AD8) and HMSE among elderly patients attending medical outpatient service (OPD) in a tertiary care hospital., Method: A total of 776 subjects aged ≥65 years and receiving treatment from medicine OPD in a tertiary care hospital were screened for dementia using AD8 and HMSE. The clinical diagnosis was established after detailed clinical assessment using ICD-10 criterion. Sensitivity and specificity were calculated for both screening tools and ROC curves were plotted considering ICD-10 diagnosis as the gold standard., Results: Comparison of receiver operating characteristic (ROC) curves showed that HMSE (AUC = 0.77) were better than AD8 (AUC = 0.61) in detecting dementia. Although increasing the cut-off value of AD8 from a recommended score of ≥2 to ≥3 improved sensitivity from 35% to 48.9%, high false-positive rate limited its utility as a cognitive screening tool., Conclusion: Although AD8 is easy to use and quickly administered with either patient or informant, it does not seem to be a suitable cognitive screening test for Indian elderly with chronic medical disorders. HMSE at a cut-off score of ≤23 is able to find out dementia among geriatric patients in a busy medical setting., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

Objective: It is common among medical students to falsely attribute bodily sensations/symptoms and holds a belief of having a medical illness with varying level of conviction. We studied and compared this condition known as "medical student syndrome", a type of hypochondriasis, between preclinical and clinical years students., Methodology: This research was a descriptive study where a total of 100 students were approached and were asked to complete a short form of health anxiety inventory (SHAI) which has Cronbach's alpha 0.855. No personal identifiers were included in the study questionnaires. All statistical analyses were performed using the SPSS statistical software package (IBM SPSS Statistics Version 23, SPSS Inc., Chicago, IL, USA)., Results: The response rate among participants was 88% (42 from preclinical and 48 from clinical years of training). Health-related anxiety (SHAI main section score ≥ 18) was found in 14.77% of students with a higher proportion in preclinical than clinical, 16.66% and 13.04%, respectively. The difference was not significant between the two groups ( χ 2 = 0.429 [1], P = 0.766). Students having medical professional in family had lower rate of health-related anxiety, χ 2 (1, n = 88) = 0.228, P = 0.633. The association between family or personal history of psychiatry or medical illness was not significant with SHAI scores. No relation was noted between current health anxiety (SHAI score) and the number of visits to the doctor per year before entering the medical course (χ = 0.174, P = 0.112)., Conclusion: Every seventh medical student was found to have health-related anxiety. It was not affected by personal and family history of either psychiatric or medical illness., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Education and Health Promotion.)

The coronavirus disease 2019 (COVID-19) pandemic has caused a major psychosocial impact in the community due to its direct effects and restrictive control strategies, e.g. lockdown. The current pandemic, a highly stressful situation, can predispose not only vulnerable but previously well-adjusted individuals for psychological disorders. A retrospective chart review of consultation-liaison psychiatry (CLP) case records was conducted for one month before and after the start of lockdown. Patients seen during lockdown were relatively younger; t = 1.8, p = 0.074. The most common psychiatric emergency was a suicidal attempt (34.3%) and delirium (35.4%) during and before lockdown, respectively. The probability of the emergency psychiatry presentation for attempted suicide increased significantly during lockdown (odds ratio (OR) 8.0, 95% CI 2.03 to 31.57, p = 0.003). The most common stressors for CLP patients with suicide attempts during lockdown were relationship issues and loss of privacy. It seems that stressors arising due to the current crisis are not only highly severe and multiple but qualitatively different. Further studies with larger sample sizes and from other parts of the country can further improve our understating of the psychological impact of the COVID-19 pandemic in the affected community. Needless to say, higher vigilance in the community for at-risk individuals, availability, and awareness about telemedicine services can play an important role to combat the risk of suicide during the lockdown., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Jhanwar et al.)

As the world struggles to control coronavirus infection with the exhausting capacity of health care systems globally, the role of primary care physician and family physician becomes more important as the first point of contact with the community. Limited availability of mental health services in India requires general practitioners to deal with psychological disorders arising due to infection outbreak and its restrictive control strategies. This article discusses what and how primary physicians can manage the psychological burden of a pandemic, and therefore, reducing the reliance on mental health specialist., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Family Medicine and Primary Care.)

Competing Interests: There are no conflicts of interest.

Background: High Von Willebrand factor (VWF) levels may predispose to multi-organ failure in acute liver failure (ALF). In rodenticide-induced hepatotoxicity patients, we analyzed if plasma VWF levels predicted survival and also the outcome of VWF lowering by N-acetyl cysteine (NAC), fresh frozen plasma (FFP) infusions, and plasma exchange (PLEX)., Methods: We retrospectively analyzed prospectively collected data. Hepatotoxicity was classified as uncomplicated acute hepatitis (UAH), acute liver injury (ALI), and ALF. ALF patients, if not opting for liver transplantation, had PLEX and NAC; ALI patients received NAC ± FFP (PLEX, if worsening); UAH patients had NAC. Plasma VWF antigen was measured (normal, 50% to 150%). In-hospital survival was analyzed as discharged alive or died/discharged in a terminal condition (poor outcome)., Results: Twenty-four consecutive rodenticide-induced hepatotoxicity patients (UAH in 1, ALI in 20, ALF in 3) from December 2017 to January 2019 were studied. Baseline VWF levels were 153%, 423 (146-890)% median (range), and 448 (414-555)% in UAH, ALI, ALF patients; model for end-stage liver disease (MELD) scores were 11, 24 (12-38), 36 (32-37) and in-hospital survival rates were 100%, 85%, 67%, respectively. VWF levels were higher in patients with poor outcome (555 [512-890]%) than in those discharged alive (414 [146-617]%) (p-value = 0.04). The area under the receiver operating curve of the VWF level, MELD score, and sequential organ failure assessment score to predict survival was 0.92, 0.84, and 0.66, respectively. Of 4 patients meeting criteria for liver transplantation (none had transplantation), 3 (75%) survived., Conclusions: High VWF levels predict poor outcome in rodenticide-induced hepatotoxicity. VWF reduction may be useful in such patients.

Purpose: In patients with chronic myelogenous leukemia (CML), point mutations in the BCR-ABL1 kinase domain are the most common cause of treatment failure with a tyrosine kinase inhibitor (TKI). It is not clear whether the splice variant BCR-ABL1(35INS) is also associated with treatment failure., Patients and Methods: We reviewed all CML patients who had BCR-ABL1 kinase mutation analysis performed between August 1, 2007, and January 15, 2014. Patients who had BCR-ABL1(35INS) detected had their medical records reviewed to determine response to TKI therapy., Results: Two hundred and eighty four patients had kinase mutation testing performed; of these, 64 patients (23%) had BCR-ABL1(35INS) detected. Forty-five patients were in chronic phase (70%), 10 were in accelerated phase (16%), 6 were in blastic phase (9%), and 3 were in other settings (5%). Of the 34 chronic phase patients who began therapy with imatinib, 23 patients (68%) failed therapy: 8 patients (24%) had primary refractory disease, 11 patients (32%) progressed, and 4 patients (12%) had disease progression after dose interruption. In contrast to the patients with disease progression or lack of response, none of 23 patients who were responding to imatinib had BCR-ABL1(35INS) detected. DNA sequencing of commonly mutated spliceosomal genes SF3B1, U2AF1, SRSF2, ZRSR2, SFA31, PRPF408, U2A565, and SF1 did not reveal mutations in seven BCR-ABL1(35INS) -positive patients tested., Conclusions: The splice variant BCR-ABL1(35INS) is frequently found in patients who are resistant to imatinib. Mutations in the commonly mutated spliceosomal proteins do not contribute to this association., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: A cancer diagnosis during adolescence or young adulthood (AYA; defined as ages 15-39) generates unique medical and psychosocial needs as developmental milestones are simultaneously impacted. Past research highlights that AYAs' experiences and psychosocial outcomes are different, and more research and attention is needed. We aimed to identify and synthesize literature regarding psychosocial outcomes, unique needs, and existing psychosocial interventions pertaining to individuals diagnosed with cancer exclusively during AYA, and to highlight areas for future research., Methods: A systematic literature search was conducted using MEDLINE (via PubMed), EMBASE, Cochrane, Web of Science, and PsycINFO (via OVID). Grey literature was searched using key term variations and combinations. Overall, 15,301 records were assessed by two independent reviewers, with 38 studies meeting inclusion criteria., Results: Data synthesis of the 38 articles was organized by four main themes based on quality of life and survivorship: physical well-being (7 studies), psychological well-being (8 studies), social well-being (9 studies), and survivorship care (14 studies). The paucity of studies for such broad inclusion criteria highlights that this population is often combined or subsumed under other age groups, missing needs unique to these AYAs., Conclusions: AYA cancer survivors' experiences are nuanced, with interacting variables contributing to post-treatment outcomes. AYAs require age-appropriate and flexible care, informational needs and treatment-related education that foster autonomy for long-term survivorship, as well as improved follow-up care and psychological outcomes., Implications for Cancer Survivors: By incorporating these findings into practice, the informational and unmet needs of AYAs can be addressed effectively. Education and programming is lacking specific and general subject matter specific to AYAs, incorporating ranging needs at different treatment stages.

Background: Patient expectations are important in bariatric and body contouring surgery because the goals include improvements in health-related quality of life, appearance, and body image. The aim of this study was to identify patient expectations along the weight loss journey and/or body contouring surgery., Methods: This qualitative study took an interpretive description approach. Between September 2009 and February 2012, 49 patients were interviewed postbody contouring surgery. Data were analyzed using a line-by-line approach whereby expectations were identified and labeled as expected, unexpected, or neutral. Constant comparison was used to ensure coding was done consistently. Interviews continued until no new themes emerged., Results: Participants described expectations according to appearance, health-related quality of life, and patient experience of care. Two areas stood out in terms of unmet expectations and included appearance and physical health, ie, recovery from body contouring surgery. Most participants, who underwent bariatric surgery, expected neither the extent of excess skin after weight loss nor how the excess skin would make them look and feel. For recovery, participants did not expect that it would be as long or as hard as it was in reality., Conclusions: A full understanding of outcomes and expectations for this patient population is needed to enhance patient education and improve shared medical decision making. Education materials should be informed by the collection of evidence-based patient-reported outcome information using measures such as the BODY-Q. A patient-reported outcome scale measuring patient expectations is needed for obese and bariatric patients.

Following chemotherapy, patients with acute myelogenous leukemia (AML), normal cytogenetics, and the FLT3-ITD mutation have shorter survival compared to wild type (WT) patients. To determine the role of stem cell transplantation (SCT), we performed a retrospective review of adult patients with AML who underwent SCT at our center between January 1, 2007 and December 31, 2011. Of the 200 patients transplanted, 79 patients (40%) had normal cytogenetics; of these, 17 (22%) had the FLT3-ITD mutation, 35 were WT (44%), and 27 (34%) did not have FLT3 testing performed. Clinical characteristics were similar in each group. At four years, overall survival (OS) between FLT3 positive and WT groups was similar: 0.54 (95% CI 0.29-0.75) versus 0.73 (95% CI 0.53-0.99), p=0.18. Relapse rates were also similar, 0.09 (95% CI 0.02-0.21) versus 0.12 (95% CI: 0.02-0.32); p=0.67. We conclude that SCT can abrogate the poor prognosis in FLT3-ITD positive patients., Competing Interests: None of the authors have a conflict of interest., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To assess demographic, medical, and psychological factors that are associated with fear of recurrence (FCR) in ovarian cancer patients., Method: We searched PubMed, EMBASE, Cochrane, CINAHL, and PsycINFO. For PubMed, a search using Medical Subject Headings (MeSH) was run, as well as a text-word search from 1990 to July of 2014. The search terms used consisted of ovarian terms, fear terms, and recurrence/progression themes. Title and abstract reviews were conducted by two independent reviewers to determine eligibility, and discrepancies were decided by a third reviewer. Full-text reviews of potentially eligible articles were conducted by the review team, which met regularly to ensure the reliability of eligibility ratings across all articles., Results: A total of 15 articles met our inclusion criteria. Nine were quantitative studies that utilized a cross-sectional design, and the other six included three qualitative studies, two small intervention studies, and one study that utilized content analysis to explore written correspondence among ovarian cancer patients. FCR was reported as a significant concern for both older and younger women at both early and advanced stages. Women were distressed about recurrence at various times during their treatment and posttreatment. FCR was noted to be prevalent around cancer follow-up examinations. Many women reported not receiving adequate support for recurrence. FCR was also shown to be linked in some way to hopelessness, faith/spirituality, and posttraumatic stress disorder (PTSD). FCR was also linked to patients' anxiety about death and dying and uncertainty about the future of their medical health., Significance of Results: This review demonstrates that FCR is prevalent in the ovarian cancer population. Moreover, cancer recurrence fears are not adequately assessed or treated. More information is needed on the factors that may be related to women's fears about recurrence of ovarian cancer. In addition, a validated measure of FCR among ovarian cancer patients as well as a treatment intervention are needed.

DNA sequencing offers a powerful tool in oncology based on the precise definition of structural rearrangements and copy number in tumor genomes. Here, we describe the development of methods to compute copy number and detect structural variants to locally reconstruct highly rearranged regions of the tumor genome with high precision from standard, short-read, paired-end sequencing datasets. We find that circular assemblies are the most parsimonious explanation for a set of highly amplified tumor regions in a subset of glioblastoma multiforme samples sequenced by The Cancer Genome Atlas (TCGA) consortium, revealing evidence for double minute chromosomes in these tumors. Further, we find that some samples harbor multiple circular amplicons and, in some cases, further rearrangements occurred after the initial amplicon-generating event. Fluorescence in situ hybridization analysis offered an initial confirmation of the presence of double minute chromosomes. Gene content in these assemblies helps identify likely driver oncogenes for these amplicons. RNA-seq data available for one double minute chromosome offered additional support for our local tumor genome assemblies, and identified the birth of a novel exon made possible through rearranged sequences present in the double minute chromosomes. Our method was also useful for analysis of a larger set of glioblastoma multiforme tumors for which exome sequencing data are available, finding evidence for oncogenic double minute chromosomes in more than 20% of clinical specimens examined, a frequency consistent with previous estimates.

Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL), but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia.

Cicer arietinum L. (chickpea) is the third most important food legume crop. We have generated the draft sequence of a desi-type chickpea genome using next-generation sequencing platforms, bacterial artificial chromosome end sequences and a genetic map. The 520-Mb assembly covers 70% of the predicted 740-Mb genome length, and more than 80% of the gene space. Genome analysis predicts the presence of 27,571 genes and 210 Mb as repeat elements. The gene expression analysis performed using 274 million RNA-Seq reads identified several tissue-specific and stress-responsive genes. Although segmental duplicated blocks are observed, the chickpea genome does not exhibit any indication of recent whole-genome duplication. Nucleotide diversity analysis provides an assessment of a narrow genetic base within the chickpea cultivars. We have developed a resource for genetic markers by comparing the genome sequences of one wild and three cultivated chickpea genotypes. The draft genome sequence is expected to facilitate genetic enhancement and breeding to develop improved chickpea varieties., (© 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.)

Previous small series have suggested that acute myeloid leukemia with t(8;16) is a distinct morphologic and clinical entity associated with poor prognosis. We describe 18 patients with t(8;16) AML, including their clinical, cytomorphologic, immunophenotypic and cytogenetic features. Half of the patients had extramedullary disease, most commonly leukemia cutis, which often preceded bone marrow involvement and six had therapy-related AML. Patients with t(8;16) AML commonly present with clinical and pathological features that mimic APL, with promyelocytes and promyeloblast-like cells and coagulopathy in most patients. Several patients also presented with marrow histiocytes with hemophagocytosis and erythrophagocytosis. Comprehensive molecular analysis for co-occurring genetic alterations revealed a somatic mutation in RUNX1 in 1 of 6 t(8;16) patients with no known AML mutation in the remaining five t(8;16) patients. This suggests that the t(8;16) translocation could be sufficient to induce hematopoietic cell transformation to AML without acquiring other genetic alteration. These data further support classifying t(8;16) AML as a clinically and molecularly defined subtype of AML marked by characteristic clinical and cytomorphologic features that mimic APL, and is associated with very poor survival., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A 4-color fluorescence in situ hybridization (FISH) assay, using probes to chromosomes 11q, 6p, 6q, and 6 cent, has recently been proposed as an ancillary tool for the diagnosis of melanoma. The authors report herein their experience with this assay. To determine the sensitivity and specificity of the assay for histopathologically unequivocal cases, they analyzed 50 melanocytic nevi, 50 primary melanomas, and 15 metastatic melanomas. Of 50 melanocytic nevi, 47 were FISH negative on initial readout (test sensitivity, 94%); 49 were FISH negative after correction for tetraploidy (test specificity, 98%). Of 50 primary melanomas, 41 were FISH positive (test sensitivity, 82%). Of 15 metastatic lesions, 13 were FISH positive (test sensitivity, 85%). Of the 9 FISH-negative melanomas, 6 metastasized. The tumors of the 5 patients who had survived thick primary melanoma for more than 5 years without recurrence were all FISH positive. Half of the patients whose primary melanoma was tested by FISH had undergone sentinel lymph node (SLN) biopsy. When the authors compared the FISH results of those 25 melanomas with the SLN status, no statistically significant correlation was found. These findings document limitations of the current FISH assay. A rare nevus may be FISH positive. Some primary metastasizing melanomas are FISH negative. Even metastatic melanomas can be FISH negative. Awareness of the limitations in test sensitivity and specificity of the FISH assay is important to avoid an erroneous diagnosis by overreliance on cytogenetic findings. Correlation with clinical and histopathological findings is paramount for accurate diagnosis.

The transcriptome of cultivated chickpea (Cicer arietinum L.), an important crop legume, has recently been sequenced. Here, we report sequencing of the transcriptome of wild chickpea, C. reticulatum (PI489777), the progenitor of cultivated chickpea, by GS-FLX 454 technology. The optimized assembly of C. reticulatum transcriptome generated 37 265 transcripts in total with an average length of 946 bp. A total of 4072 simple sequence repeats (SSRs) could be identified in these transcript sequences, of which at least 561 SSRs were polymorphic between C. arietinum and C. reticulatum. In addition, a total of 36 446 single-nucleotide polymorphisms (SNPs) were identified after optimization of probability score, quality score, read depth and consensus base ratio. Several of these SSRs and SNPs could be associated with tissue-specific and transcription factor encoding transcripts. A high proportion (92-94%) of polymorphic SSRs and SNPs identified between the two chickpea species were validated successfully. Further, the estimation of synonymous substitution rates of orthologous transcript pairs suggested that the speciation event for divergence of C. arietinum and C. reticulatum may have happened approximately 0.53 million years ago. The results of our study provide a rich resource for exploiting genetic variations in chickpea for breeding programmes., (© 2012 The Authors. Plant Biotechnology Journal © 2012 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.)

Metastatic lesions of malignant melanoma can on occasion be difficult to classify with regard to the primary site of origin. Given the lack of specificity of light microscopic features, ancillary studies are needed. In this study, the authors explored the possibility of distinguishing metastatic tumors derived from uveal primaries from those known to have originated from a cutaneous melanoma by fluorescence in situ hybridization (FISH) using probes for chromosome 3, 8q24, and 1p36. A total of 32 metastatic tumors were analyzed by FISH. Monosomy 3 was detected in 9 out of 16 (56.3%) cases of metastatic uveal melanoma but was not found in any of the 16 metastatic cutaneous melanomas (P < .001). With regard to 1p36, amplifications were found in 8 out of 16 (50%) cases of metastatic cutaneous melanoma but not in any case of uveal melanoma (P < .05). 1p36 was deleted in 3 cases of uveal and 1 case of cutaneous melanoma. Amplifications of 8q were found in 15 out of 16 (94%) cases of uveal melanoma metastases and in 12 out of 16 (75%) cases of cutaneous metastases. The findings suggest that FISH for monosomy 3 is a useful adjunct tool in the differential diagnosis of metastatic uveal versus cutaneous melanoma.

Metastatic melanoma can on rare occasion simulate the appearance of a blue nevus clinically and/or histopathologically, which may lead to diagnostic confusion and delay in treatment. Given the known difficulty in recognizing a small dermal blue nevus-like melanoma metastasis by light microscopic findings alone, recent discoveries of unique cytogenetic aberrations in various types of melanomas have led pathologists to explore cytogenetic techniques as an ancillary diagnostic tool. Herein, we report a case of a 58-year-old man with a history of uveal melanoma, in which fluorescence in situ hybridization (FISH) analysis for monosomy 3 helped confirm a diagnosis of blue nevus-like uveal melanoma metastasis. The patient had presented clinically with a new small 1-mm dark blue-gray macule on the forehead. Histopathologically, a small dermal nodule of pigmented epithelioid melanocytes and melanophages was found with a rare mitotic figure. The pathologist's suspicion of a blue nevus-like melanoma metastasis was confirmed by FISH analysis: both the tumor cells of the patient's prior uveal melanoma and the melanocytes of the new dermal blue nevus-like nodule carried only one copy of chromosome 3. Furthermore, deletion of 1p36 and amplifications of 8q32 were also identified., (Copyright © 2012 John Wiley & Sons A/S.)

Glioblastoma (GBM) is distinguished by a high degree of intratumoral heterogeneity, which extends to the pattern of expression and amplification of receptor tyrosine kinases (RTKs). Although most GBMs harbor RTK amplifications, clinical trials of small-molecule inhibitors targeting individual RTKs have been disappointing to date. Activation of multiple RTKs within individual GBMs provides a theoretical mechanism of resistance; however, the spectrum of functional RTK dependence among tumor cell subpopulations in actual tumors is unknown. We investigated the pattern of heterogeneity of RTK amplification and functional RTK dependence in GBM tumor cell subpopulations. Analysis of The Cancer Genome Atlas GBM dataset identified 34 of 463 cases showing independent focal amplification of two or more RTKs, most commonly platelet-derived growth factor receptor α (PDGFRA) and epidermal growth factor receptor (EGFR). Dual-color fluorescence in situ hybridization was performed on eight samples with EGFR and PDGFRA amplification, revealing distinct tumor cell subpopulations amplified for only one RTK; in all cases these predominated over cells amplified for both. Cell lines derived from coamplified tumors exhibited genotype selection under RTK-targeted ligand stimulation or pharmacologic inhibition in vitro. Simultaneous inhibition of both EGFR and PDGFR was necessary for abrogation of PI3 kinase pathway activity in the mixed population. DNA sequencing of isolated subpopulations establishes a common clonal origin consistent with late or ongoing divergence of RTK genotype. This phenomenon is especially common among tumors with PDGFRA amplification: overall, 43% of PDGFRA-amplified GBM were found to have amplification of EGFR or the hepatocyte growth factor receptor gene (MET) as well.

We evaluated sequential bortezomib, liposomal doxorubicin and dexamethasone (BDD) followed by thalidomide and dexamethasone (TD) if ≥ partial response (PR) or bortezomib and TD (BTD) if < PR in untreated patients with multiple myeloma with International Staging System stage II/III or extramedullary disease. Of the 42 patients enrolled, two-thirds had cytogenetic abnormalities including high-risk findings [del(13q) by karyotype, t(4;14), loss of p53 or gain 1q] in one-third. After the planned three cycles of BDD, the overall response rate (ORR) was 81% with 40% ≥ very good partial response (VGPR), including 26% near complete and complete responses (nCR/CR). After the additional two cycles of TD or BTD, ORR was 83% with 60% ≥ VGPR including 43% nCR/CR, indicating deeper responses following sequential therapy (p = 0.008). Two-thirds of patients who presented with significant renal impairment had improved renal function. All patients undergoing stem cell harvest had a successful collection. BDD followed by TD or BTD is effective initial therapy for this population with higher-risk myeloma and results in rapid disease control and a high response rate.

Chickpea (Cicer arietinum L.) is an important crop legume plant with high nutritional value. The transcriptomes of desi and wild chickpea have already been sequenced. In this study, we sequenced the transcriptome of kabuli chickpea, C. arietinum (genotype ICCV2), having higher commercial value, using GS-FLX Roche 454 and Illumina technologies. The assemblies of both Roche 454 and Illumina datasets were optimized using various assembly programs and parameters. The final optimized hybrid assembly generated 43,389 transcripts with an average length of 1065 bp and N50 length of 1653 bp representing 46.2 Mb of kabuli chickpea transcriptome. We identified a total of 5409 simple sequence repeats (SSRs) in these transcript sequences. Among these, at least 130 and 493 SSRs were polymorphic with desi (ICC4958) and wild (PI489777) chickpea, respectively. In addition, a total of 1986 and 37,954 single nucleotide polymorphisms (SNPs) were predicted in kabuli/desi and kabuli/wild genotypes, respectively. The SNP frequency was 0.043 SNP per kb for kabuli/desi and 0.821 SNP per kb for kabuli/wild, reflecting very low genetic diversity in chickpea. Further, SSRs and SNPs present in tissue-specific and transcription factor encoding transcripts have been identified. The experimental validation of a selected set of polymorphic SSRs and SNPs exhibited high intra-specific polymorphism potential between desi and kabuli chickpea, suggesting their utility in large-scale genotyping applications. The kabuli chickpea gene index assembled, and SSRs and SNPs identified in this study will serve as useful genomic resource for genetic improvement of chickpea.