p16 gene homozygous deletions in acute lymphoblastic leukemia

The p16 protein is a cyclin inhibitor encoded by a gene located in 9p21, which may have antioncogenic properties, and is inactivated by homozygous p16 gene deletion or, less often, point mutation in several types of solid tumors often associated to cytogenetic evidence of 9p21 deletion. We looked for homozygous deletion and point mutation of the p16 gene in acute lymphoblastic leukemia (ALL), where 9p21 deletion or rearrangement are also nonrandom cytogenetic findings. Other hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), and myeloma were also studied. Homozygous deletion of the p16 gene was seen in 9 of the 63 (14%) ALL analyzed, including 6/39 precursor B-ALL, 3/12 T-ALL, and 0/12 Burkitt's ALL. Three of the 7 ALL with 9p rearrangement (including 3 of the 5 patients where this rearrangement was clearly associated to 9p21 monosomy) had homozygous deletion compared to 5 of the 55 patients with normal 9p (the last patient with homozygous deletion was not successfully karyotyped). Single stranded conformation polymorphism analysis of exons 1 and 2 of the p16 gene was performed in 88 cases of ALL, including the 63 patients analyzed by Southern blot. Twenty-six of the cases had 9p rearrangement, associated to 9p21 monosomy in at least 12 cases. A missense point mutation, at codon 49 (nucleotide 164), was seen in only 1 of the 88 patients. No homozygous deletion and no point mutation of the p16 gene was seen in AML, MDS, CLL, and myeloma. Homozygous deletion of interferon alpha genes (situated close to p16 gene in 9p21) was seen in only 3 of the 9 ALL patients with p16 gene homozygous deletion, and none of the ALL without p16 gene homozygous deletion. Our findings suggest that homozygous deletion of the p16 gene is seen in about 15% of ALL cases, is not restricted to cases with cytogenetically detectable 9p deletion, and could have a pathogenetic role in this malignancy. On the other hand, p16 point mutations are very rare in ALL, and we found no p16 homozygous deletions or mutations in the other hematologic malignancies studied.     

Additive effect of erythropoietin and heme on murine hematopoietic recovery after azidothymidine treatment [see comments]

The ability of combination treatment with erythropoietin (Epo) and heme to rescue hematopoietic activity in mice from the suppressive effect of azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked anemia, thrombocytopenia, neutropenia, and weight loss, whereas mice that received Epo and heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT- treated animals and reduced the severe anemia and thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced anemia, although, when combined with heme, there was a great improvement in recovery of erythropoiesis. The combination of heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus, heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT therapy.     

Predictive value for treatment outcome in acute myeloid leukemia of cellular daunorubicin accumulation and P-glycoprotein expression simultaneously determined by flow cytometry

To evaluate the clinical relevance of multidrug resistance (MDR) phenotype, the intracellular daunorubicin accumulation (IDA) and P- glycoprotein (P-gp) expression were investigated in 87 adult patients with acute leukemia: 69 patients with de novo acute myeloid leukemia (AML), 10 with AML at relapse, and eight with secondary leukemia to myelodysplastic syndromes (MDS-AML). IDA and P-gp expression were determined by double-labeling flow cytometry analysis. Of 87 patients, 36 expressed P-gp (41%). P-gp expression was more frequently observed in AML at relapse and MDS-AML as compared with de novo AML (P = .0001). P-gp expression was significantly associated with CD34 expression (P = .0003) and chromosome 7 abnormalities (P = .027). A significantly reduced IDA was observed in P-gp+ as compared with P-gp- patients (P = .0007). Of the 87 patients, 51 achieved complete remission (CR). A reduced IDA was observed in patients in failure as compared with patients in CR (22% +/- 17% v 42% +/- 21%; P = 10(-4). Twelve of 36 P- gp+ patients as compared with 40 of 51 P-gp- patients achieved CR (33% v 78%; P = 10(-4). The prognostic value of IDA and P-gp expression was confirmed in multivariate analysis. These data suggest that the determination of IDA and P-gp expression may be useful in designing therapy for patients with AML.     

Cancer Prevention and Screening for Older Adults: Part 1. Lung,Colorectal, Bladder,and Kidney Cancer

The incidence of most cancers increases with age. Cancer is the second most common cause of death in older adults after cardiovascular disease. Many common cancers in older adults can be prevented from occurring or can be identified at an early stage and treated effectively. The prevention and identification of cancer in its early stages, in an attempt to reduce discomfort and disability associated with advanced cancer and cancer treatment, is also a priority. Overscreening for cancer in older adults can lead to unnecessary diagnostic testing and unnecessary treatment. Both older adults and their healthcare providers need guidance on the appropriate use of cancer prevention and screening interventions. This first of a two-part review addresses special considerations regarding cancer prevention for adults aged 65 and older. Screening decisions and the impact of limited life expectancy and an older adult's ability to tolerate cancer treatment are also addressed. Guidance is provided regarding the prevention and early identification of lung, colorectal, bladder, and kidney cancer in older adults. The prevention of breast, prostate, and female urogenital cancers are addressed in Part 2. J Am Geriatr Soc 68:2399–2406, 2020.     

Control of hypertension with medication: a comparative analysis of national surveys in 20 countries

Objective

To examine hypertension management across countries and over time using consistent and comparable methods.

Methods

A systematic search identified nationally representative health examination surveys from 20 countries containing data from 1980 to 2011 on blood pressure measurements, the diagnosis and treatment of hypertension and its control with antihypertensive drugs. For each country, the prevalence of hypertension (i.e. systolic blood pressure ≥ 140 mmHg or antihypertensive use) and the proportion of hypertensive individuals whose condition was diagnosed, treated or controlled with medications (i.e. systolic pressure < 140 mmHg) were estimated.

Findings

The age-standardized prevalence of hypertension varied between countries: for individuals aged 35 to 49 years, it ranged from around 12% in Bangladesh, Egypt and Thailand to around 30% in Armenia, Lesotho and Ukraine; for those aged 35 to 84 years, it ranged from 20% in Bangladesh to more than 40% in Germany, the Russian Federation and Turkey. The age-standardized percentage of hypertensive individuals whose condition was diagnosed, treated or controlled was highest in the United States of America: for those aged 35 to 49 years, it was 84%, 77% and 56%, respectively. Percentages were especially low in Albania, Armenia, the Islamic Republic of Iran and Turkey. Although recent trends in prevalence differed in England, Japan and the United States, treatment coverage and hypertension control improved over time, particularly in England.

Conclusion

Globally the proportion of hypertensive individuals whose condition is treated or controlled with medication remains low. Greater efforts are needed to improve hypertension control, which would reduce the burden of noncommunicable diseases.     

VHSV G glycoprotein major determinants implicated in triggering the host type I IFN antiviral response as DNA vaccine molecular adjuvants

We have recently identified the two major determinants of the glycoprotein G of the viral hemorrhagic septicaemia rhabdovirus (gpG_VHSV), peptides p31 and p33 implicated in triggering the host type I IFN antiviral response associated to these rhabdoviral antigens. With the aim to investigate the properties of these viral glycoprotein regions as DNA molecular adjuvants, their corresponding cDNA sequences were cloned into a plasmid (pMCV1.4) flanked by the signal peptide and transmembrane sequences of gpG_VHSV. In addition, a plasmid construct encoding both sequences p31 and p33 (pMCV1.4-p31 + p33) was also designed. In vitro transitory cell transfection assays showed that these VHSV gpG regions were able to induce the expression of type I IFN stimulated genes as well as to confer resistance to the infection with a different fish rhabdovirus, the spring viremia of carp virus (SVCV). In vivo, zebrafish intramuscular injection of only 1 μg of the construct pMCV1.4-p31 + p33 conferred fish protection against SVCV lethal challenge up to 45 days post-immunization. Moreover, pMCV1.4-p31 + p33 construct was assayed for molecular adjuvantcity's for a DNA vaccine against SVCV based in the surface antigen of this virus (pAE6-G_SVCV). The results showed that the co-injection of the SVCV DNA vaccine and the molecular adjuvant allowed (i) a ten-fold reduction in the dose of pAE6-Gsvcv without compromising its efficacy (ii) an increase in the duration of protection, and (iii) an increase in the survival rate. To our knowledge, this is the first report in which specific IFN-inducing regions from a viral gpG are used to design more-efficient and cost–effective viral vaccines, as well as to improve our knowledge on how to stimulate the innate immune system.     

Thromboprophylaxis in a patient with COVID‐19 and severe hemophilia A on emicizumab prophylaxis

COVID‐19 can be associated with coagulopathy (CAC, COVID‐19‐associated coagulopathy) with a high prothrombotic risk based on an intense inflammatory response to viral infection leading to immunothrombosis through different procoagulant pathways. Emerging evidence suggests that the use of heparin in these patients could be associated with lower mortality. Emicizumab is a bispecific humanized monoclonal antibody that bridges activated factor IX and factor X, thereby restoring the function of missing factor VIIIa in hemophilia A. The use of emicizumab has been associated with thrombotic events in patients who also received high cumulative amounts of activated prothrombin complex concentrates. Although this risk is extremely low, there is a lack of evidence on whether CAC increases the thrombotic risk in patients on emicizumab prophylaxis. We present the case of a patient with severe hemophilia A in prophylaxis treatment with emicizumab; due to the potential thrombotic risk we decided to administer low molecular weight heparin as prophylaxis treatment without any thrombotic or bleeding complications.     

B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells

The purpose of this study was to analyze the expression of B cell growth factor (BCGF) receptors and to elucidate the biologic effects of biochemically purified natural BCGF at the B cell precursor stage of human B lineage lymphoid differentiation. The specific binding of radioiodinated high-mol-wt BCGF (125I-HMW-BCGF) and low-molecular-wt BCGF (125I-LMW-BCGF) to fresh marrow blasts from B cell precursor acute lymphoblastic leukemia (ALL) patients was initially investigated. The estimated number of radioiodinated BCGF molecules bound per blast ranged from undetectable to 24.3 X 10(3) for HMW-BCGF, and from 11.5 X 10(3) to 457.8 X 10(3) for LMW-BCGF. In 3H-TdR incorporation assays, 75% of cases showed a significant response to LMW-BCGF with a median stimulation index of 9.3. By comparison, only 33% of cases showed a significant response to HMW-BCGF with a median stimulation index of 2.4. Subsequently, B cell precursor colony assays were performed to assess and compare the biologic effects of BCGF on leukemic B lineage lymphoid progenitor cells. Among 28 cases studied, 57% responded to both HMW-BCGF and LMW-BCGF, 21% responded only to LMW-BCGF, and the remaining cases showed no proliferative response to either growth factor. The response patterns of virtually pure populations of FACS- sorted leukemic B cell precursors were essentially identical to the proliferative responses of unsorted leukemic B-cell precursors. Synergistic effects between HMW-BCGF and LMW-BCGF were observed in 80% of the cases that responded to both. The numbers of cell-bound radioiodinated BCGF molecules, the stimulation indices, as well as the number of B cell precursor colonies in BCGF-stimulated cultures showed a marked interpatient variation. Patients with structural chromosomal abnormalities (SCAs) involving 12p11-13 or patients with a Philadelphia chromosome showed a greater HMW-BCGF response at the level of leukemic progenitor cells than did other patients (P = .02). The LMW-BCGF response was significantly greater for patients with SCA than for patients without SCA (P = .04). The response of leukemic progenitor cells to HMW-BCGF or LMW-BCGF did not correlate with sex, age, disease status, FAB morphology, WBC at diagnosis, or immunophenotype. To our knowledge, this study represents the first detailed analyses of BCGF receptor expression and BCGF effects in B cell precursor ALL. The data presented provide direct evidence for the expression of functional receptors for both HMW-BCGF and LMW-BCGF in B cell precursor ALL.     

Treatment with amniopatch of premature rupture of membranes after first-trimester chorionic villus sampling

OBJECTIVE: To assess the amniopatch procedure when premature rupture of membranes occurs after first-trimester chorionic villus sampling (CVS). STUDY DESIGN: From May 2001 to June 2004, the amniopatch procedure was offered in cases of premature rupture of membranes after CVS when severe oligohydramnios was present (largest vertical pocket < 2 cm) and persistent (more than 1 week). RESULTS: The amniopatch was placed in five pregnancies at 12-18 weeks of gestation, resulting in amniotic fluid restoration in all but one pregnancy. In three pregnancies, fetal demise was observed at 1, 2 and 36 days after the procedure. The last procedure resulted in a healthy newborn. CONCLUSION: Although the amniopatch restored normal amniotic fluid levels in all cases, 4 of the 5 cases resulted in fetal demise.     

Epidemiology of tuberculosis and HIV coinfections in Singapore, 2000–2014

Cross‐matching of records between Singapore's tuberculosis and HIV registries showed that 3.3% of individuals with tuberculosis (TB) were coinfected with HIV (2000?2014), the TB incidence among individuals with HIV infection was 1.65 per 100 person‐years, and 53% of coinfections were diagnosed within 1 month of each other. The findings supported joint prevention programmes for early diagnosis and treatment.