On the Order of Gene Distribution on Chromosomes Across the Animal Kingdom

Background. The large-scale pattern of distribution of genes on the chromosomes in the known animal genomes is not well characterized. We hypothesized that individual genes will be distributed on chromosomes in a mathematically ordered manner across the animal kingdom. Results. Twenty-one animal genomes reported in the NCBI database were examined. Numerically, there was a trend towards increasing overall gene content with increasing size of the genome as reflected by the chromosomal complement. Gene frequency on individual chromosomes in each animal genome was analyzed and demonstrated uniformity of proportions within each animal with respect to both average gene frequency on individual chromosomes and gene distribution across the unique genomes. Further, average gene distribution across animal species followed a relationship whereby it was, approximately, inversely proportional to the square root of the number of chromosomes in the unique animal genomes, consistent with the notion that there is an ordered increase in gene dispersion as the complexity of the genome increased. To further corroborate these findings a derived measure, termed gene spacing on chromosomes correlated with gene frequency and gene distribution. Conclusion. As animal species have evolved, the distribution of their genes on individual chromosomes and within their genomes, when viewed on a large scale is not random, but follows a mathematically ordered process, such that as the complexity of the organism increases, the genes become less densely distributed on the chromosomes and more dispersed across the genome.Comment: 13 pages, 3 tables and 7 figure

SCT Question 11

Question 11 A 65 Y male presents for a clinic visit and reports slowly progressive dyspnea on exertion, with cough evolving over the last week. SaO2 on RA is 88% and drops to 82% with walking, with a 30 beats per minute increase in HR. SaO2 returns to baseline over two minutes upon coming to rest. He underwent a HLA-A antigen mismatched unrelated donor transplant using a reduced intensity conditioning regimen for high-risk AML in CR2, four months ago. GVHD ppx was with PT CY followed by MMF and tacrolimus, early post-transplant course was complicated by asymptomatic CMV viremia which was treated with oral valganciclovir. Because of high-risk disease tacrolimus was stopped at day 90 post-transplant. Lung exam reveals crackles in bilateral bases. There is no JVD or peripheral edema. Heart sounds are normal. There is no skin rash. CT of the chest without contrast demonstrates scattered bilateral areas of consolidation. Galactomannan assay is negative. CRP is 4xULN. What is the most likely successful treatment 1. FAM therapy 2. Foscarnet 3. Levofloxacin 4. Prednisone       5. Posaconazole Answer Option 4. This is a case of organizing pneumonia in a patient who has had an HLA mismatched unrelated donor transplant, with early withdrawal of immune suppression to provoke a graft vs. leukemia effect in relapsed high-risk AML. The clinical course was complicated by CMV viremia which further increases the risk for alloreactive response in an already fraught setting. Several weeks later he has progressive dyspnea and severe hypoxia with hemodynamic consequences, elevated CRP and has consolidation on chest CT scan. This situation requires systemic corticosteroids. FAM will be inadequate therapy given consolidative changes. In practice the CT findings merit antibiotic therapy to be commenced as well. This measure of hypoxia will usually be seen in more advanced fungal disease. Nevertheless, BAL is a necessary part of the work up. Foscarnet administration will need evidence of active CMV infection. At day 100 off tacrolimus CMV pneumonia is less likely

SCT Question 16

Question 16 A 45-year female was transplanted with a HLA-haploidentical donor (her 20-year-old son) and is now day 15 post-transplant. She is to be transfused today for a Hemoglobin of 6.5 G/dL, her ANC is 0.8/cmm and PL are 20,000/cmm. She is A- and the donor is B+, reticulocyte count is still Type A- PRBC Type B+ PRBC Type AB- PRBC Type O- PRBC Type O+ PRBC Answer Option 4. This donor has bidirectional ABO incompatibility (B transplanted into A) with the donor, in this instance her Rh+ son. Cross match compatible type O blood will be the safest option since residual recipient derived anti B and evolving donor derived anti A will not impact the transfused red cells. She has still not had myeloid engraftment so going with donor blood is not appropriate, and transfusion of recipient blood type risks a donor immune response

SCT Question 5

Question 5 During morning rounds a 40 Y/M patient with AML, who underwent myeloablative conditioning with Busulfan and cyclophosphamide, followed by a HLA matched unrelated donor transplant 11 days ago, complains of RUQ pain of moderate severity and asks for pain medications. He is lethargic today compared to his usual very active normal self. There is tenderness in the RUQ, a distinct liver edge is not palpable because of moderate abdominal distension. Flank dullness is noted on percussion. There is no JVD, but there is pitting lower extremity edema. A review of weight charts shows a 10% weight increase over the admission weight, despite patient not taking anything (including medicines) by mouth for the last four days due to mucositis. Nurses report that he has not had an adequate transfusion response to platelet transfusions for two days in a row (\u3c10K rise in the 30 min post transfusion PL ct.). Bilirubin is 6 on this morning\u27s blood draw and predominantly conjugated. Alk phos 3xULN; ALT and AST are both 4xULN. PT is prolonged, with mildly elevated D-Dimer. Creatinine is elevated at 2.5, and urine FENA is \u3c1. A review of pre-transplant therapy reveals that he had received gemtuzumab as a part of his induction. Abd US with hepatic vascular dopplers shows reversal of portal venous flow and elevated hepatic artery resistive index, as well as confirming hepatomegaly and ascites Your next most effective intervention will be 1. Resume oral ursodiol and start IV heparin 2. Start IV defibrotide with adequate platelet transfusion support 3. Discontinue TPN and diurese with furosemide 4. Obtain transjugular liver biopsy with portal venous pressure measurement 5. Stop azole antifungals. Answer Option 2. This is a case of severe sinusoidal obstruction syndrome, or veno-occlusive disease, as a result of endothelial injury in the zone 3 of hepatic sinusoids. Classically busulfan depletes glutathione stores resulting in accumulation of cyclophosphamide intermediate metabolites which cause endothelial injury (greater concentration in the center of the hepatic lobule). This patient has VOD with evolving multiorgan failure, encephalopathy and renal insufficiency. He has several of the clinical features of VOD, including transfusion refractory thrombocytopenia. In the pre-defibrotide days, these patients had a dismal prognosis with the vast majority either not surviving MOF or if they did survive with supportive care, then later on succumbing to complications of portal HTN. Defibrotide is a complex mixture of single stranded polydeoxyribonucleotides derived from porcine intestinal mucosa that has antithrombotic and profibrinolytic activity and is used in the treatment of severe sinusoidal obstruction syndrome (SOS) after hematopoietic cell transplantation (HCT). (PUBCHEM). Patients with severe VOD treated early following onset, and occasionally beyond the FDA approved 21 days of treatment may have a significant likelihood of resolution of VOD and surviving this complication. Diuresis and fluid management are the other cornerstones of VOD Rx. Ursodiol helps prevent hepatic complications posttransplant by limiting intrahepatic cholestasis. Discontinuation of any hepatotoxic medications is prudent to minimize further liver injury, but not likely to alter the natural course of VOD/SOS, which of the listed options, only defibrotide can do

SCT Question 2

Question 2 You are asked to evaluate a patient receiving GCSF for hematopoietic stem cell mobilization. This is a 65-year-old patient, weighing 100 KG, with a h/o transformed follicular lymphoma who is in complete remission. This is the fifth day of GCSF 960 micrograms SC daily for stem cell mobilization. Yesterday you had seen him for persistent, throbbing pain in his back, sternum and ribs which responded to acetaminophen. Today he c/o moderate LUQ and mild L shoulder pain, which is persistent. He is not in distress and vital signs are at the upper limit of normal range for both HR and BP, RR is 24 with normal SaO2 and body temperature. There is mild LUQ tenderness on exam, without palpable organomegaly. WBC ct. is 45,000/microL, blood CD34+ cell ct. is 40/microL. What is your next Rx step? Perform a sepsis evaluation and start broad spectrum antibiotics Stop GCSF and cancel apheresis Obtain CT CAP to evaluate relapsed NHL Give GCSF and proceed with apheresis Hold GCSF and proceed with apheresis Answer Q2 Option 5. This patient has developed splenomegaly while getting 10 micrograms/kg/d GCSF for stem cell mobilization, although not commonly seen this may be complicated by splenic rupture. This patient is mildly symptomatic and hemodynamically stable so the likelihood of this severe complication is low. The blood CD34+ cell count predicts optimal timing for stem cell collection, therefore the patient should proceed with apheresis with careful observation. Abdominal imaging will be appropriate to rule out splenic pathology, but stem cell collection should be prioritized to avoid missing the window of optimal yield. Given splenic symptoms and adequate CD34+ cells in circulation, the GCSF administration may be deferred until stem cell yield of the procedure is known that afternoon

SCT Question 18

Question 18 A 65-year-old patient is 88 days post unrelated donor PBSC transplant. Conditioning was with Bu-Flu and ATG was given from day -9 to day -7, followed by tacrolimus and MMF. Grade III skin/GI GVHD developed after withdrawal of MMF and was treated with MP and eventually ruxolitinib due to steroid refractoriness. Ruxolitinib yields a good response and now the patient is asymptomatic and presents too the clinic for a routine visit. Current immune suppression is with ruxolitinib, tacrolimus and steroids are being tapered. EBV titer last week was detectable but not quantifiable. Today the titer is 500 copies/mL. There is no fever or lymphadenopathy, LDH is normal, and no atypical lymphocytosis is observed. He is HLA-A2 positive. Next treatment options are Continue 3 agent immunosuppression and repeat EBV in one week Taper immunosuppression over two weeks and repeat EBV Administer rituximab and taper steroids over two weeks Administer EBV specific, HLA-A2 cytotoxic CTL Administer IV IGG Answer Option 3. This patient has had in vivo T cell depletion utilizing ATG and is now on three agent immunosuppression with steroids, ruxolitinib and CNI for management of steroid refractory GVHD. The EBV titer has risen significantly and with this background is likely to continue going up exponentially and thus requires therapy. Rapid tapering of immune suppression risks a flare of severe GI GVHD and IV IGG is ineffective