Publications by authors named "Alma Imamovic"

12 Publications

  • Page 1 of 1

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

N Engl J Med 2021 11;385(22):2059-2065

From the Departments of Pediatric Oncology (J.K., K.V.H., J.A.P., C.M.C., A.I., C.B.W., K.A.J., S.G.D.) and Medical Oncology (W.G.K.), Dana-Farber Cancer Institute, Harvard Medical School, the Divisions of Hematology and Oncology (J.K., J.A.P., M.M.H., K.A.J., S.G.D.) and Endocrinology (A.J.W.) and the Departments of Surgery (B.R.W.), Pathology (S.O.V.), and Radiology (S.D.V.), Boston Children's Hospital, Harvard Medical School, and the Manton Center for Orphan Disease Research and the Division of Genetics and Genomics, Boston Children's Hospital (J.A.M., J.L.) - all in Boston; Howard Hughes Medical Institute, Chevy Chase, MD (W.G.K.); and Merck, Kenilworth, NJ (R.F.P., N.J.Z.).

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in . Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2110051DOI Listing
November 2021

Gene Fusions Create Partner and Collateral Dependencies Essential to Cancer Cell Survival.

Cancer Res 2021 Aug 7;81(15):3971-3984. Epub 2021 Jun 7.

Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

Gene fusions frequently result from rearrangements in cancer genomes. In many instances, gene fusions play an important role in oncogenesis; in other instances, they are thought to be passenger events. Although regulatory element rearrangements and copy number alterations resulting from these structural variants are known to lead to transcriptional dysregulation across cancers, the extent to which these events result in functional dependencies with an impact on cancer cell survival is variable. Here we used CRISPR-Cas9 dependency screens to evaluate the fitness impact of 3,277 fusions across 645 cell lines from the Cancer Dependency Map. We found that 35% of cell lines harbored either a fusion partner dependency or a collateral dependency on a gene within the same topologically associating domain as a fusion partner. Fusion-associated dependencies revealed numerous novel oncogenic drivers and clinically translatable alterations. Broadly, fusions can result in partner and collateral dependencies that have biological and clinical relevance across cancer types. SIGNIFICANCE: This study provides insights into how fusions contribute to fitness in different cancer contexts beyond partner-gene activation events, identifying partner and collateral dependencies that may have direct implications for clinical care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-21-0791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338889PMC
August 2021

Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium.

Cancer Discov 2021 Jun 9;11(6):1424-1439. Epub 2021 Feb 9.

Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations...
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-20-0564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178162PMC
June 2021

Integrated genetic and pharmacologic interrogation of rare cancers.

Nat Commun 2016 06 22;7:11987. Epub 2016 Jun 22.

Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.

Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this cancer, which has no known alterations in these genes. These observations establish an approach that integrates new patient-derived models, functional genomics and chemical screens to facilitate the discovery of targets in rare cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms11987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917959PMC
June 2016

A comparative assessment of clinical whole exome and transcriptome profiling across sequencing centers: implications for precision cancer medicine.

Oncotarget 2016 Aug;7(33):52888-52899

Department of Urology, University of Washington, Seattle, 98195, WA, USA.

Advances in next generation sequencing technologies provide approaches to comprehensively determine genomic alterations within a tumor that occur as a cause or consequence of neoplastic growth. Though providers offering various cancer genomics assays have multiplied, the level of reproducibility in terms of the technical sensitivity and the conclusions resulting from the data analyses have not been assessed.We sought to determine the reproducibility of ascertaining tumor genome aberrations using whole exome sequencing (WES) and RNAseq. Samples of the same metastatic tumors were independently processed and subjected to WES of tumor and constitutional DNA, and RNAseq of RNA, at two sequencing centers. Overall, the sequencing results were highly comparable. Concordant mutation calls ranged from 88% to 93% of all variants including 100% agreement across 154 cancer-associated genes. Regions of copy losses and gains were uniformly identified and called by each sequencing center and chromosomal plots showed nearly identical patterns. Transcript abundance levels also exhibited a high degree of concordance (r2 ≥ 0.78;Pearson). Biologically-relevant gene fusion events were concordantly called. Exome sequencing of germline DNA samples provided a minimum of 30X coverage depth across 56 genes where incidental findings are recommended to be reported. One possible pathogenic variant in the APC gene was identified by both sequencing centers.The findings from this study demonstrate that results of somatic and germline sequencing are highly concordant across sequencing centers that have substantial experience in the technological requirements for preparing, sequencing and annotating DNA and RNA from human biospecimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.9184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288156PMC
August 2016

Genome update of the dimorphic human pathogenic fungi causing paracoccidioidomycosis.

PLoS Negl Trop Dis 2014 Dec 4;8(12):e3348. Epub 2014 Dec 4.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.

Paracoccidiodomycosis (PCM) is a clinically important fungal disease that can acquire serious systemic forms and is caused by the thermodimorphic fungal Paracoccidioides spp. PCM is a tropical disease that is endemic in Latin America, where up to ten million people are infected; 80% of reported cases occur in Brazil, followed by Colombia and Venezuela. To enable genomic studies and to better characterize the pathogenesis of this dimorphic fungus, two reference strains of P. brasiliensis (Pb03, Pb18) and one strain of P. lutzii (Pb01) were sequenced [1]. While the initial draft assemblies were accurate in large scale structure and had high overall base quality, the sequences had frequent small scale defects such as poor quality stretches, unknown bases (N's), and artifactual deletions or nucleotide duplications, all of which caused larger scale errors in predicted gene structures. Since assembly consensus errors can now be addressed using next generation sequencing (NGS) in combination with recent methods allowing systematic assembly improvement, we re-sequenced the three reference strains of Paracoccidioides spp. using Illumina technology. We utilized the high sequencing depth to re-evaluate and improve the original assemblies generated from Sanger sequence reads, and obtained more complete and accurate reference assemblies. The new assemblies led to improved transcript predictions for the vast majority of genes of these reference strains, and often substantially corrected gene structures. These include several genes that are central to virulence or expressed during the pathogenic yeast stage in Paracoccidioides and other fungi, such as HSP90, RYP1-3, BAD1, catalase B, alpha-1,3-glucan synthase and the beta glucan synthase target gene FKS1. The improvement and validation of these reference sequences will now allow more accurate genome-based analyses. To our knowledge, this is one of the first reports of a fully automated and quality-assessed upgrade of a genome assembly and annotation for a non-model fungus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0003348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256289PMC
December 2014

Complete genome sequence of Algoriphagus sp. PR1, bacterial prey of a colony-forming choanoflagellate.

J Bacteriol 2011 Mar 23;193(6):1485-6. Epub 2010 Dec 23.

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA.

Bacteria are the primary food source of choanoflagellates, the closest known relatives of animals. Studying signaling interactions between the Gram-negative Bacteroidetes bacterium Algoriphagus sp. PR1 and its predator, the choanoflagellate Salpingoeca rosetta, provides a promising avenue for testing hypotheses regarding the involvement of bacteria in animal evolution. Here we announce the complete genome sequence of Algoriphagus sp. PR1 and initial findings from its annotation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JB.01421-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3067637PMC
March 2011

Comparison of the effects of Puumala and Dobrava viruses on early and long-term renal outcomes in patients with haemorrhagic fever with renal syndrome.

Nephrology (Carlton) 2010 Apr;15(3):340-3

University Clinical Centre Tuzla, Bosnia and Herzegovina.

Aim: The clinical course and outcome of patients with haemorrhagic fever with renal syndrome (HFRS) caused by Puumala (PUUV) and Dobrava viruses (DOBV) were analyzed and whether it left long-term consequences on kidney function after 10 years was evaluated.

Methods: Cross-sectional studies were conducted to test the kidney function and blood pressure of HFRS-affected patients and to follow them up 10 years after. Eighty-two PUUV- and 53 DOBV-induced HFRS patients and 14 and 31 participants 10 years after having contracted PUUV- and DOBV-related diseases, respectively were evaluated.

Results: Serum creatinine concentrations were 279.5 and 410 mcmol/L in PUUV and DOBV groups, respectively (P = 0.005). There were six and 13 anuric (P < 0.05), none and seven dialysis-dependant (P < 0.05), and nine and 18 hypotensive patients (P < 0.05) in PUUV and DOBV groups, respectively. After 10 years, glomerular filtration rates were 122.1 + or - 11.1 and 104.7 + or - 20.2 mL/min (P < 0.05) in PUUV and DOBV groups, respectively.

Conclusion: During the acute phase, DOBV causes more severe renal impairment than PUUV infection. After 10 years follow up, renal function was found within normal limits, although after DOBV infection glomerular filtration rate (GFR) was significantly lower than after PUUV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1440-1797.2009.01195.xDOI Listing
April 2010

Importance of isolation and biotypization of Gardnerella vaginalis in diagnosis of bacterial vaginosis.

Bosn J Basic Med Sci 2008 Aug;8(3):270-6

Polyclinic for Laboratory Diagnostics, Department for Microbiology, University Clinics Centre Tuzla, Trnovac bb, 75 000 Tuzla, Bosnia and Herzegovina.

The natural habitat of Gardnerella vaginalis is a vagina since it could be located among 69% of women who have no signs of vaginal infection and in the vagina of as many as 13.5% girls. G. vaginalis is almost certainly identified among women diagnosed with bacterial vaginosis as well as in the urethra of their sexual partner. The increase in prevalence and concentration of G. vaginalis among patients diagnosed with this syndrome confirms that G. vaginalis plays a significant role in its pathogenesis. In our research, based on Amsel criteria for three or more clinical signs of bacterial vaginosis, it was diagnosed in 20.5% of women with subjective problems of vaginal infection, and in 48.80% of women with subjective symptoms characteristic of this disease. G. vaginalis was isolated from vaginal secretion of women without clinical signs characteristic of bacterial vaginosis. In 2.58% of cases it was solitary, while in 1.28% it was found in combination with other aerobic and anaerobic bacteria and, in 1.28% women combined with Candida albicans. The isolation of G. vaginalis was significantly increased (p<0.05) in the group of women with clinical signs of bacterial vaginosis in comparison to the group of women without these signs. Frequent recurrence of bacterial vaginosis, which is found in 20-30% of women within a three months treatment, is explained as reinfection with other biotype of G. vaginalis, different from a source biotype or as a consequence of wrong treatment. Following Piot biotype scheme, biotypes 2., 3. and 7. G. vaginalis are significantly more often isolated from women who suffer from bacterial vaginosis. Biotype 7. G. vaginalis, isolated from the group of women without clinical signs of bacterial vaginosis, accounted for 2.58% cases. Following Benit biotype scheme, biotypes IVa, IVc and IIc were identified in 12.90% cases, while biotypes IIIa, IIa, Ia, IVb, IIb were found in 6.45% cases. Lipase-positive isolates of G. vaginalis were significantly more frequently accompanied by the syndrome of bacterial vaginosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694681PMC
http://dx.doi.org/10.17305/bjbms.2008.2932DOI Listing
August 2008

Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men.

Bone 2007 Mar 28;40(3):587-96. Epub 2006 Nov 28.

Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA 02131, USA.

Polymorphisms in the LRP5 gene have been associated with bone mineral density (BMD) in men and/or women. However, the functional basis for this association remains obscure. We hypothesized that LRP5 alleles could modulate Wnt signaling and the relationship between physical activity and BMD. This genetic association study was performed in the population-based Framingham Study Offspring Cohort, and included a subset of 1797 unrelated individuals who provided blood samples for DNA and who had BMD measurements of the hip and spine. Ten single-nucleotide polymorphisms (SNPs) spanning the LRP5 gene were genotyped and used for association and interaction analyses with BMD by regression methods. LRP5 haplotypes were transiently co-expressed with Wnt3a, MesD and Dkk1 in HEK293 cells and their activity evaluated by the TCF-Lef reporter assay. Six out of ten SNPs in LRP5 were associated with one or more of the femur or spine BMDs in men or women after adjustment for covariates, and these associations differed between genders. In men< or =age 60 years, 3 SNPs were significantly associated with BMD: rs2306862 on Exon 10 with femoral neck BMD (p=0.01) and Ward's BMD (p=0.01); rs4988321/p. V667M with Ward's BMD (p=0.02); and intronic rs901825 with trochanter BMD (p=0.03). In women, 3 SNPs in intron 2 were significantly associated with BMD: rs4988330 for trochanter (p=0.01) and spine BMD (p=0.003); rs312778 with femoral neck BMD (p=0.05); and rs4988331 with spine BMD (p=0.04). For each additional rare allele, BMD changed by 3-5% in males and 2-4% in females. Moreover, there was a significant interaction between physical activity and rs2306862 in exon 10 (p for interaction=0.02) and rs3736228/p. A1330V in exon 18 (p for interaction=0.05) on spine BMD in men. In both cases, the TT genotype was associated with lower BMD in men with higher physical activity scores, conversely with higher BMD in men with lower physical activity scores. In vitro, TCF-Lef activity in presence of Wnt3a was significantly reduced in cells expressing LRP5 haplotypes carrying the T allele of exon 10 and 18 compared to the wild-type allele, whereas co-expression of Dkk1 completely inhibited Wnt3a response through all LRP5 haplotypes. In summary, genetic variation in exons 10 and 18 of the LRP5 gene modulates Wnt signaling and the relationship between physical activity and BMD in men. These observations suggest that Wnt-LRP5 may play a role in the adaptation of bone to mechanical load in humans, and may explain some gender-related differences in bone mass.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2006.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1845172PMC
March 2007

[Diagnostical values of antibody on A60 antigen in diagnostic of tuberculosis].

Med Arh 2006 ;60(3):166-70

Poliklinika za Mikrobiologiju, Patologiju, Imunologiju I Molekularnu Medicinu, JZU Univerzitetsko Klinicki Centar Tuzla.

Aim of this research was to investigate diagnostic value of discovering of antibody on A60 antigen in patients who were tested for presents of Mycobacterium tuberculosis in there biological samples. We tested a samples of sputum, gastric juice, urine, cerebrospinal fluid and punctate from group of 353 patients who were suspected for tuberculosis. In all patients we were looking for antibodies classes A60 antigen. We used immune chromatographic "Hexagon TB" test, Germane company "Human Geselschaft fur Biochemica und Diagnostica". From 353 patients we found 58 (16.43%) patients with positive BK, 79/22,38%) patients with positive Lowenstein culture and 122 (34,55%) patients with antibody in sera on A60 antigen. Patients who were BK and Lowenstein positive, have had antibody in 94,23% cases, Patients who were BK negative and Lowenstein positive have had antibodies in 70,37% cases and patients who were BK negative and Lowenstein negative have had antibody in 19,03% cases. Patients with BK positive and Lowenstein negative results have had antibody in 50,00% cases. Difference between results is significant (p<0,01). From 122 patients with positive antibodies, 52 were BK positive and 68 have had positive Lowenstein cultures. From 231 patients with no antibody, just 6 were BK positive and 11 Lowenstein positive. In 62 patients with positive antibodies, were BK and Lowenstein negative. We confirmed that antibody on A60 antigen in microbiological positive patients are more often then in microbiological negative patients (p<0,001).
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2006

[Prevalence of patients infected with resistant strain of Mycobacterium tuberculosis in Canton Tuzla].

Med Arh 2005 ;59(5):293-6

Poliklinika za mikrobiologiju, patologiju, imunologiju i molekularnu biologiju JZU Univerzitetsko klinicki centar Tuzla.

Aim of this work is to show the level of prevalence of patients infected with resistant strains Mycobacterium tuberculosis in Canton Tuzla. In the period of 1996-2003 year we tested 87,408 samples of different materials on existence of Mycobacterium tuberculosis. Among all samples there were 66,128 sputum, 14,599 urines, 3,817 gastric juice, 1,174 materials from broncholavage and 547 other samples. Microscopically it was found 4,380 smear-positive samples and 6,365 samples were positive on Loewenstein medium. Positive sputum had 1,917 patients, and positive culture had 3,018 patients. Resistance test was done on streptomycin, isoniazid, rifampicin and ethambutol with standard proportional method for 2,662 patients. Totally sensibile were 2,570 or 96.54%, and restant were 92 or 3.46% patients. Patients infected with mono-drug resistant strains Mycobacterium tuberculosis were 71 or 2.67%, and poli-drugs resitant 21 or 0.78%. There were 16 patients or 0.60% infected with multi-drugs resistant strains. Time of bacteriological negativization for the patients infected with resistant strains was in the average 8.19 months, for the patients infected with mono-drug resistant strains was 2.75 months and for infected with multi-drugs resistant strains was 32 months. It is concluded that region of Canton Tuzla has high level of bacteriological prevalence but low level of prevalence of patients infected with resistant strains Mycobacterium tuberculosis in the this period of time, and it is significantly lower then earlier periods, thanks to national tuberculosis control program and system of directly observed treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
November 2005
-->