Acute Myeloid Leukemia is a kind of fatal blood cancer with a high death rate caused by abnormal cells’ rapid growth in the human body. The usual method to detect AML is the manual microscopic examination of the blood sample, which is tedious and time-consuming and requires a skilled medical operator for accurate detection. In this work, we proposed an AlexNet-based classification model to detect Acute Myeloid Leukemia in microscopic blood images and compared its (...) performance with LeNet-5-based model in Precision, Recall, Accuracy, and Quadratic Loss. The experiments are conducted on a dataset of four thousand blood smear samples. The results show that AlexNet was able to identify 88.9% of images correctly with 87.4% precision and 98.58% accuracy, whereas LeNet-5 correctly identified 85.3% of images with 83.6% precision and 96.25% accuracy. (shrink)

Mutations in the CEBPA gene are present in 10–15% of acute myeloid leukemia (AML) patients. The most frequent type of mutations leads to the expression of an N‐terminally truncated variant of the transcription factor CCAAT/enhancer‐binding protein alpha (C/EBPα), termed p30. While initial reports proposed that p30 represents a dominant‐negative version of the wild‐type C/EBPα protein, other studies show that p30 retains the capacity to actively regulate gene expression. Recent global transcriptomic and epigenomic analyses have advanced the understanding (...) of the distinct roles of the p30 isoform in leukemogenesis. This review outlines direct and indirect effects of the C/EBPα p30 variant on oncogenic transformation of hematopoietic progenitor cells and discusses how studies of N‐terminal CEBPA mutations in AML can be extrapolated to identify novel gain‐of‐function features in oncoproteins that arise from recurrent truncating mutations in transcription factors. (shrink)

The DNA hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DAC) improve survival and transfusion independence in myelodysplastic syndrome (MDS) and enable a low intensity cytotoxic treatment for aged AML patients unsuitable for intensive chemotherapy, particularly in combination with novel agents. The proposed mechanism of AZA and DAC relies on active DNA replication and therefore patient responses are only observed after multiple cycles of treatment. Although extended dosing may provide the optimal scheduling, the reliance of injectable formulation of the drug limits (...) it to intermittent treatment. Recently, an oral formulation of AZA demonstrated significantly improved patient relapse free survival (RFS) and overall survival (OS) when used as maintenance after chemotherapy for AML. In addition, both DAC and AZA were found to be highly effective to improve survival in elderly patients with AML through combination with other drugs. These recent exciting results have changed the therapeutic paradigm for elderly patients with AML. In light of this, we review current knowledge on HMA mechanism of action, clinical trials exploring dosing and scheduling, and recent HMA combination therapies to enhance efficacy. (shrink)

Diagnostik und Klassifikation der akuten myeloischen Leukämie (AML) beruhen auf zytologischen und zytogenetischen Charakteristika. Eine Individualisierung der Diagnostik und Therapie wird für AML mit normalem Karyotyp (CN-AML) durch den Nachweis spezifischer Genmutationen zunehmend ermöglicht. In einem systematischen Literaturreview und Metanalyse wurde die Mutation FLT3-ITD bei CN-AML untersucht. Eine systematische Literaturrecherche aller Veröffentlichungen der Datenbanken Embase, Pubmed, Healthstar, BIOSIS, ISI Web of Knowledge und Cochrane wurde für den Zeitraum 2000 bis März 2012 im Hinblick auf die Mutation FLT3-ITD bei Patienten mit (...) CN-AML und einem Alter von 15–65 Jahren durchgeführt. Der Literaturrecherche folgte eine Literaturselektion, eine Datenextraktion und eine qualitative sowie quantitative Informationssynthese in Form einer Metaanalyse. Achtzehn Veröffentlichungen konnten in die qualitative Analyse zur CN-AML eingeschlossen werden. Daten von 3 Publikationen zum Gesamtüberleben mit insgesamt 1.203 Patienten gingen mit Bezug auf den Marker FLT3-ITD in die Metaanalyse ein. Für FLT3-ITD zeigte sich eine statistisch signifikante schlechtere Prognose mit einer hazard ratio von 2,19 für das Gesamtüberleben bei CN-AML. FLT3-ITD ist im Vergleich zum Wildtyp mit einer schlechteren Prognose in Bezug auf den Krankheitsverlauf bei AML assoziiert. Die Analyse von FLT3 sollte bei der AML berücksichtigt werden. (shrink)

Chronic myeloid leukemia (CML) is a cancer of the hematopoietic system initiated by a single genetic mutation which results in the oncogenic fusion protein Bcr-Abl. Untreated, patients pass through different phases of the disease beginning with the rather asymptomatic chronic phase and ultimately culminating into blast crisis, an acute leukemia resembling phase with a very high mortality. Although many processes underlying the chronic phase are well understood, the exact mechanisms of disease progression to blast crisis are (...) not yet revealed. In this paper we develop a mathematical model of CML based on causal Bayesian networks in order to study possible disease progression mechanisms. Our results indicate that an increase of Bcr-Abl levels alone is not sufficient to explain the phenotype of blast crisis and that secondary changes such as additional mutations are necessary to explain disease progression and the poor therapy response of patients in blast crisis. (shrink)

Hematopoiesis is the complex developmental process through which undifferentiated, pluripotent, hematopoietic stem cells come to generate mature, functional blood cells. This process is regulated in large part by specific transcription factors that control expression of genes necessary for the developmental sequence. Leukemias represent one form of disruption of this normal developmental process, and studies over the past few years have shown that many of the genes that underlay leukemogenesis are also essential for normal hematopoiesis. In an interesting recent example, Song (...) et al.(1) demonstrate that haploinsufficiency of the AML1 gene is the genetic basis of a form of familial thrombocytopenia which predisposes the affected individuals to the development of acute myeloid leukemia. Here we summarize Song's paper and current information describing the interesting dosage effects of this gene and other members of its gene family. BioEssays 22:214–218, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

When positionally cloned in late 1989, it was anticipated that mutations within the Wilms' tumour suppressor gene (WT1) would prove responsible for this common solid kidney cancer of childhood. Characterisation of the WT1 expression pattern and of the structure of the encoded protein isoforms and their mode of action has now spanned almost a decade. WT1 proteins act as nucleic acid-binding zinc finger-containing transcription factors involved in both transactivation and repression. These activities are facilitated and constrained by interactions with other (...) proteins. Expression analyses and knockout mice indicate that WT1 protein plays a critical role in normal kidney and gonad development. Specific constitutional WT1 mutations results in several urogenital anomaly syndromes. While only 10% of sporadic Wilms' tumours do display WT1 mutation, WT1 is mutated in other cancers, including acute myeloid leukaemia. Much is still to be determined in WT1 biology. The next decade will see at least three streams of attention. The first two, elucidation of the role of WT1 in RNA metabolism and the characterisation of further protein partners, may together explain the distinct tissue-specific functions of WT1. Finally, further research into the role of WT1 in haematopoiesis will improve our understanding of WT1 in leukaemia. BioEssays 21:191-202, 1999. (C) 1999 John Wiley & Sons, Inc. (shrink)

Refusing treatment for potentially curable childhood cancers engenders much discussion and debate. I present a case in which the competent parents of a young Amish child with acute myeloid leukemia deferred authority for decision making to the child’s maternal grandfather, who was vocal in his opposition to treatment. I analyze three related concerns that distinguish this case from other accounts of refused treatment.First, I place deference to grandparents as decision makers in the context of surrogate decision making (...) more generally.Second, the maternal grandfather’s ardent refusal of treatment and his rationale appeared to be inconsistent with the beliefs expressed by other family members and by members of the same Amish community, leading members of the medical team to question whether refusal of treatment should be treated differently when it appears to be based on the idiosyncratic beliefs of an individual rather than on community-wide values.Third, the medical team perceived tension and dissension between the nonverbal behavior of some family members and the verbal statements made by the maternal grandfather, leading the team to question the parents’ true wishes and debate how to weigh nonverbal and indirect forms of communication.Finally, building upon the conclusions of these queries, I explore whether, if the child’s prognosis was less favorable or if he were to relapse later, the maternal grandfather should have been permitted to drive a decision to refuse further treatment. (shrink)

Aging of the organism is associated with highly reproducible DNA methylation (DNAm) changes, which facilitate estimation of donor age. Cancer is also associated with DNAm changes, which may contribute to disease development. Here, we speculate that age‐associated DNAm changes may increase the risk of tumor initiation. Notably, when using epigenetic signatures for age‐estimations tumor cells are often predicted to be much older than the chronological age of the patient. We demonstrate that aberrant hypermethylation within the gene DNA methyltransferase 3A (DNMT3A) (...) – which may contribute to initiation of acute myeloid leukemia (AML) – is particularly observed in AML samples that reveal significantly more age‐associated DNAm changes. The functional relevance of age‐associated DNAm changes remains to be elucidated, but they occur genome wide, in a highly reproducible manner, and most likely influence chromatin organization – and hence may favor acquisition of aberrant DNAm patterns contributing to cancer in the elderly. (shrink)

I had been on the phone with Madeleine's mother for fifteen minutes, and she had sobbed throughout. She pleaded with me, “You won't even let our family visit her together. If you really want to help my daughter, you will let us stay with her.” Madeleine, who was twenty‐four years old, was dying of end‐stage acute myeloid leukemia and was intubated in one of our intensive care units. Her intensivist had requested a clinical ethics consultation for potentially (...) inappropriate medical treatment—in my world of clinical ethics consultation, routine stuff. Except that, in March 2020, nothing was routine anymore. The Covid‐19 pandemic calls for creative thinking about ad hoc and post hoc bereavement efforts, and it may result in efforts to revise existing accounts of what constitutes a good death in order to accommodate patients’ and families’ experiences at the end of life during a pandemic. (shrink)

Lei, a twenty‐seven‐year‐old Mandarin speaker, visits the United States seeking curative treatments for his acute myeloid leukemia. His mother, Hua, has traveled with him. Neither she nor Lei speak English, and the hospital does not have an onsite professional Mandarin‐speaking interpreter. Using a professional interpreter over the phone, Lei's oncologist, Dr. Branson, attempts to initiate a face‐to‐face goals‐of‐care conversation with Hua as the surrogate decision‐maker. Dr. Branson explains that Lei has “only weeks to months to live” and (...) recommends initiating comfort‐care‐only measures, but Hua says that she wants (and that Lei would want) continued aggressive measures. Hua says that her son might be a candidate for a phase I trial. Eventually, Dr. Branson brings in Dr. Chou, a Mandarin‐speaking resident to provide face‐to‐face interpretation. Hua insists that “there must be more standard therapies available” and says that she will wait until the trial begins. She begins crying, and the meeting disintegrates. Following this, Dr. Branson calls for an ethics consultation for “help in end‐of‐life communicating and reconciling discordance about prognostic information.”How should the ethicist use the institution's interpreter services? (shrink)

Recent findings position the eukaryotic translation initiation factor eIF4E as a novel modulator of mRNA splicing, a process that impacts the form and function of resultant proteins. eIF4E physically interacts with the spliceosome and with some intron‐containing transcripts implying a direct role in some splicing events. Moreover, eIF4E drives the production of key components of the splicing machinery underpinning larger scale impacts on splicing. These drive eIF4E‐dependent reprogramming of the splicing signature. This work completes a series of studies demonstrating eIF4E (...) acts in all the major mRNA maturation steps whereby eIF4E drives production of the RNA processing machinery and escorts some transcripts through various maturation steps. In this way, eIF4E couples the mRNA processing‐export‐translation axis linking nuclear mRNA processing to cytoplasmic translation. eIF4E elevation is linked to worse outcomes in acute myeloid leukemia patients where these activities are dysregulated. Understanding these effects provides new insight into post‐transcriptional control and eIF4E‐driven cancers. (shrink)

B‐cell acute lymphoblastic leukaemia (B‐ALL) is a clonal malignant disease originated in a single cell and characterized by the accumulation of blast cells that are phenotypically reminiscent of normal stages of B‐cell differentiation. B‐ALL origin has been a subject of continuing discussion, given the fact that human disease is diagnosed at late stages and cannot be monitored during its natural evolution from its cell of origin, although most B‐ALLs probably start off with chromosomal changes in haematopoietic stem cells. However, (...) the cells responsible for maintaining the disease appear to differ between the different types of B‐ALLs and this remains an intriguing and exciting topic of research, since these cells have been posited to be responsible for resistance to conventional therapies, recurrence and dissemination. During the last years this problem has been addressed primarily by transplantation of purified subpopulations of human B‐ALL cells into immunodeficient mice. The results from these different reconstitution experiments and their interpretations are compared in this review in the context of normal B‐cell developmental plasticity. While the results from different research groups might appear mutually exclusive, we discuss how they could be reconciled with the biology of normal B‐cells and propose research avenues for addressing these issues in the future. (shrink)

Abstractβ‐Catenin/CTNNB1 is critical for leukemia initiation or the stem cell capacity of several hematological malignancies. This review focuses on a general evaluation of β‐catenin function in normal T‐cell development and T‐cell acute lymphoblastic leukemia (T‐ALL). The integration of the existing literature offers a state‐of‐the‐art dissection of the complexity of β‐catenin function in leukemia initiation and maintenance in both Notch‐dependent and independent contexts. In addition, β‐catenin mutations are screened for in T‐ALL primary samples, and it is found (...) that they are rare and with little clinical relevance. Transcriptional analysis of Wnt family members (Ctnnb1, Axin2, Tcf7, and Lef1) and Myc in different publicly available T‐ALL cohorts indicates that the expression of these genes may correlate with T‐ALL subtypes and/or therapy outcomes. (shrink)

B‐cell Acute Lymphoblastic Leukemia (B‐ALL) is the most common pediatric cancer, arising most often in children aged 2–5 years. This distinctive age distribution hints at an association between B‐ALL development and disrupted immune system function during a susceptible period during childhood, possibly triggered by early exposure to infection. While cure rates for childhood B‐ALL surpass 90% in high‐income nations, survivors suffer from diminished quality of life due to the side effects of treatment. Consequently, understanding the origins and evolution (...) of B‐ALL, and how to prevent this prevalent childhood cancer, is paramount to alleviate this substantial health burden. This article provides an overview of our current understanding of the etiology of childhood B‐ALL and explores how this knowledge can inform preventive strategies. (shrink)

Objective: This study examined the process through which elderly patients with new-onset acute leukemia make treatment decisions from the time of diagnosis, in order to identify factors influencing this decision-making process in Japan. Methods: Semi-structured interviews were conducted with twenty-two elderly patients with leukemia. The data were analyzed using the modified grounded theory approach. Results: The process of decision-making in elderly patients with leukemia includes three stages: Initial reactions at diagnosis, change in attitudes, and entrusting the (...) physician with the treatment plan. Initial reactions at diagnosis were affected by interactions with others that brought peace of mind to the patients. Change in attitudes was affected by encouragement from others to undergo treatment and their own motivation to face treatment. Patients came to entrust their treatment plan completely to their physician, because they wanted to feel relief and did not want to have to grapple with difficult medical information that was relevant to decision-making about their disease and treatment options. Conclusions: The process of decision-making in elderly patients with leukemia is affected by several factors and included three stages. Our present study findings can provide suggestions on how medical professionals might better support the process of decision-making in elderly patients with leukemia. (shrink)

While outcomes for children with T-cell acute lymphoblastic leukemia have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor T-ALLs as well as in (...) a subset of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.Leukemia advance online publication, 30 May 2017; doi:10.1038/leu.2017.136. (shrink)

The ability to improve diagnosis and refine prognosis in children with acute leukaemia is improving steadily. A growing number of tests can and are being performed on leukaemic cells. These include surface-marker analysis, DNA content, cytogenetics and studies of gene rearrangements. Increasingly large bone-marrow samples, now usually obtained under general anaesthesia, are required to make secure diagnoses. Ethical issues arise from three major areas. 1) Current research on leukaemia cells requested by the Medical Research Council is considered by local (...) research ethics committees, but parents are not regularly given detailed information about or asked specifically to consent to such research; 2) substantial quantities of excess cells are stored indefinitely. This archive of stored material is a valuable resource for research but there has been little consideration of the ethical issues which arise from this practice, and 3) there is a potential for pressure to obtain increasingly large samples. 'Creeping growth' in sample size is likely to continue unless ethics committees consider future research proposals in more detail. These issues deserve attention in order that worthwhile research and its publication are not impeded for want of ethical consideration. The implications extend beyond the field of childhood leukaemia. (shrink)

Mixed lineage leukemia (MLL) fusion protein (FP)‐induced acute leukemia is highly aggressive and often refractory to therapy. Recent progress in the field has unraveled novel mechanisms and targets to combat this disease. Menin, a nuclear protein, interacts with wild‐type (WT) MLL, MLL‐FPs, and other partners such as the chromatin‐associated protein LEDGF and the transcription factor C‐Myb to promote leukemogenesis. The newly solved co‐crystal structure illustrating the menin–MLL interaction, coupled with the role of menin in recruiting both WT (...) MLL and MLL‐FPs to target genes, highlights menin as a scaffold protein and a central hub controlling this type of leukemia. The menin/WT MLL/MLL‐FP hub may also cooperate with several signaling pathways, including Wnt, GSK3, and bromodomain‐containing Brd4‐related pathways to sustain MLL‐FP‐induced leukemogenesis, revealing new therapeutic targets to improve the treatment of MLL‐FP leukemias. (shrink)

Cell lines and cell samples from patients provide opportunities for studying the mechanisms of leukemic cellular differentiation and proliferation. Phorbol esters and 1,25 dihydroxy vitamin D3 can induce differentiation of myeloid leukemic cells to macrophages. Differentiation to granulocytes can be induced by several different compounds. Myeloid differentiation is associated closely with the alteration in expression of several oncogenes. These regulatory events may be associated with the extent of methylation, unfolding or association of chromatin to the nuclear matrix. Oncogene (...) amplification, mutation, or deletion can occur with malignant transformation. Future studies point to the development of specific pharmacological agents which can modify the neoplastic transformation. (shrink)

Physiological concentrations of retinoic acid can induce acute alterations in the expression of the enzyme tissue transglutaminase in cultured macrophages. The induction of this enzyme offers a probe to study the mechanism of retinoid action in both normal and leukemic cells.

In lieu of an abstract, here is a brief excerpt of the content:Cracked ArmorJoanne AlfredDisclaimers. Names have been changed to protect the privacy of the patient and the patient's family.After three weeks of night shifts, I had built a routine of driving home in darkness and watching the sunrise. It had become my way to push back against a quiet melancholy, the accumulation of loss over time, by remembering that light gently returning each morning. Heading into my last stretch of (...) ten nights in a row, I was intent to hold to this practice, to anchor myself for the challenge. The one-and-a-half years of residency training had prepared me for these moments, opportunities to grow and persist. The first six days of the stretch passed as I had expected, and the confidence and autonomy I had cultivated carried me through. It always had. I had shouldered our neurosurgery service, solitary night shifts at community hospitals, the NICU. I had pronounced a newborn dead on Good Friday, heartbroken by the juxtaposition of life and death. My experiences allowed tears and doubts, but I had always rebounded, chin up and looking onward for the next thing.I had just received sign out, and needed to check on Nate, a young man I'd known since he was first diagnosed with T-cell acute lymphoblastic leukemia (T-Cell ALL). I remembered our first meeting, a new diagnosis with a white cell count in the thousands requiring PICU admission for plasma exchange, all the way to reassuring him his EKG was normal after an incidental finding of hyperkalemia. He had returned to the hospital with abdominal swelling, and dread filled me as I rounded the corner to his room. Looking down at him and back up at his mother, my own distress reflected in their eyes. We needed help. I quickly found the oncology fellow and attending, and we put our heads together, deciding a blood gas and X-ray would be the next best steps. The results confirmed our suspicions.Nate was transferred to the PICU shortly. I watched his mother console him, remembering how much they both disliked the PICU. It was not a [End Page 85] place of pleasant memories, especially as Nate had been working toward remission therapy rather than returning to the intensive care unit, where he fought through his initial diagnosis. While reassuring him and his mother externally, internally my own dread welled further, because my first night in the PICU loomed two days away. To bolster myself for my seventh night shift, I rounded with the PICU team to learn as much as I could. Nate was on BIPAP now, and the decision inexorably moved to intubation. It was all happening rapidly, and the dread started feeling more like panic. Nate's eyes were squeezed shut, his stomach taut, and his breathing shallow. I truly worried for Nate now. I had hoped the PICU would be a temporary stay, a place where we could make a diagnosis and fill the gap. However, when I joined the private conversation the PICU attending had with Nate's mother and she said, "He may never come off the ventilator. He may never speak again," the finality in her voice had more certainty.The "never" struck my brittle residency armor and it cracked. I was not ready to believe it. I could sense his mother felt the same, so we walked along the silent halls of the hospital while she remembered Nate with me as a teenage boy beyond the hospital, not as his ascites and acidosis. Maybe to make his turn for the worse untrue. But I knew something awful was going to happen.On my eighth night, I entered the PICU with trepidation. All I could think about was Nate. He was now on dialysis, struggling with true hyperkalemia. Turning the corner to the unit, my heart racing, begging please don't let him die. It was hard to sense in the moment, but the cumulative melancholy, the sense that it could be held back, was not holding true. So, I defaulted to my splintering armor of persistence, picking apart his labs, discussing his dialysis with the nephrology fellow. I put my head down... (shrink)

According to the somatic mutation theory (SMT), cancer begins with a genetic change in a single cell that passes it on to its progeny, thereby generating a clone of malignant cells. It is strongly supported by observations of leukemias that bear specific chromosome translocations, such as Burkitt's lymphoma, in which a translocation activates the c‐myc gene, and chronic myeloid leukemia (CML), in which the Philadelphia chromosome causes production of the BCR‐ABL oncoprotein. Although the SMT has been modified and (...) extended to encompass tumor suppressor genes, epigenetic inheritance, and tumor progression through accumulation of further mutations, perhaps the strongest validation comes from the successful treatment of certain malignancies with drugs that directly target the product of the mutant gene.magnified imageDavid Vaux is at the Walter and Eliza Hall Institute and La Trobe Institute for Molecular Science, Melbourne, Australia. (shrink)

The child was 2 years, 8 months old and weighed 25 pounds, one-fifth the weight of her mother, for whom she was to be the bone marrow donor. The mother had suffered a relapse of acute myelogenous leukemia; her physicians recommended a bone marrow transplant. The child was the closest human leukocyte antigen match and thus the best donor candidate for her mother's transplant.

BACKGROUND: The offer of return of research results to study participants has many potential benefits. The current study examined the offer of return of research results by analyzing consent forms from 2 acute lymphoblastic leukemia studies of the 235 institutional members of the Children's Oncology Group. METHODS: Institutional review board (IRB)-approved consent forms from 2 standard-risk acute lymphoblastic leukemia studies (Children's Cancer Group [CCG] 1991 and Pediatric Oncology Group [POG] 9407) were analyzed independently by 2 reviewers. (...) RESULTS: The authors received replies from 202 of the 235 institutions that were contacted (85%). One hundred eighty-one institutions had CCG 1991 (n = 96) or POG 9905 (n = 85) protocols that were approved by an IRB. Most institutions provided contact information for the principal investigator (n = 175; 97%) and a member of the institution's research services office (n = 154; 85%). Only 5 (2.8%) institutions provided an indication of a participant's right to receive a summary of research results; most of these institutions provided details on how (n = 5) or when (n = 5) this was to occur. All of these institutions (n = 162; 89.5%) provided a specific statement offering new information that might affect a participant's decision to continue to participate in a study. Only 2 institutional consent forms offered participants the option to receive research results, and only 10 (5.5%) consent forms contained an unambiguous, specific statement offering to provide new information after the study was closed. CONCLUSIONS: Few institutional review board-approved consent forms explicitly indicate the right of research recipients to receive a summary of the results of the research in which they have participated. (shrink)

When The Emperor of All Maladies was published in late 2010, I knew it would be near the top of my stack of books to read. Since I am a PhD student in the History of Science and Medicine, reading a notable book on the history of cancer and its treatments is a must. Sadly, at the time of its publication, my mother had just died unexpectedly at age 82 of a disease for which she had never received a prior (...) diagnosis: cancer, or acute myelogenous leukemia, to be exact. From diagnosis to death took a mere six days. So I hesitated to take this in-depth look at cancer, a disease that left my family and me stunned and grieving from such a sudden loss. I reasoned, however, that the approach of the book would be detached and scientific, perhaps similar to the tone of the academic tomes that I tackle each week. I began to read. (shrink)

Clonal disease is often regarded as almost synonymous with cancer. However, it is becoming increasingly clear that our bodies harbor numerous mutant clones that are not tumors, and mostly give rise to no disease at all. Here we discuss three somatic mutations arising within the hematopoietic system: BCR‐ABL, characteristic of chronic myeloid leukemia; mutations of the PIG‐A gene, characteristic of paroxysmal nocturnal hemoglobinuria; the V617F mutation in the JAK2 gene, characteristic of myeloproliferative diseases. The population frequencies of these (...) three blood disorders fit well with a hierarchical model of hematopoiesis. The fate of any mutant clone will depend on the target cell and on the fitness advantage, if any, that the mutation confers on the cell. In general, we can expect that only a mutation in a hematopoietic stem cell will give long‐term disease; the same mutation taking place in a cell located more downstream may produce just a ripple in the hematopoietic ocean. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Bringing Cancer Care to Those who Don't Have ItLawrence N. ShulmanI have been treating cancer patients in the Harvard Medical School hospitals since 1977, and in those 35 years we have made tremendous progress. Though work still needs to be done, and far too many patients still die of cancer, many are cured. In particular, children and young adults have a high rate of cure from such diseases as (...) Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and childhood sarcoma. Patients with breast cancer in the US have a greater than 80% chance for long-term survival. The death rate from cervical cancer in the US is very low. These results have been achieved by making diagnoses earlier, in many cases surgical excision, and often systemic therapies such as chemotherapy, hormonal therapy, radiation therapy, and more recently by using so-called "targeted" therapies—those directed at particular molecular characteristics of the cancer cells.Princess Dina Mired has said that the opportunity to survive cancer should not be an accident of geography. In cases where we already have effective and inexpensive tools to cure cancer, these treatments should be considered a basic human right, a life-saving medical service.I met Patty, a young woman living in the U.S. during November of her senior year in high school, after she discovered a small lump above her left collar bone. Though she felt entirely well, she called her primary care doctor who saw her the next day, felt the enlarged lymph node, and referred her to a surgeon, who did a biopsy later that week. Her primary care doctor also called me, and we scheduled a visit when the pathology results were available. The following week the pathologist notified Patty's pediatrician that the biopsy showed Hodgkin's lymphoma. When I met Patty, she was a bright and focused young woman, waiting to hear about her college applications and enjoying her senior year. Her cancer diagnosis was completely out of context with her life as she planned it, but with the support of her family and boyfriend, she seemed prepared to take things one step at a time. A PET CT scan demonstrated a modest mass in the mediastinum (chest), but no other disease. She was in an early stage of the disease with an excellent prognosis. We recommended and administered six months of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine—four chemotherapy agents that are off-patent, and relatively inexpensive. She lost her hair, not a trivial issue for her, but otherwise felt reasonably well during the treatment. She was determined to graduate with her classmates, and was able continue to attend school and keep up with her work. In June, seven months into her cancer diagnosis and treatment, she graduated with honors, and was on track to enroll in college in September.Like other 18-year-old women with Hodgkin's lymphoma, Patty had an over 80% chance for cure with the potential for a long and productive life ahead of her because we could perform a biopsy, make a diagnosis, and safely and effectively treat her with four inexpensive, off-patent, chemotherapy drugs. She had nearly the same likelihood of living a long and fruitful life as her classmates, and had the same chances for childbearing. In my line of work, with the knowledge we now possess, to allow someone like Patty to die without a chance of curative care is simply unacceptable. Treatment of curable cancers should be considered on par with the right to clean water, adequate nutrition, treatment for infectious disease, and access to maternal and child healthcare services.But in many places in the world, people with cancers we could easily eradicate in Boston have no access to cancer services, and do die unnecessarily. The local healthcare infrastructure has no [End Page E10] capacity to evaluate a patient, perform or process a biopsy, make a diagnosis, or treat the patient with potentially curative surgery, chemotherapy and radiation. I have rounded on the wards of hospitals in developing countries, stopping to talk with numerous patients like Patty: young women, some of whom might have had Hodgkin's lymphoma, but no... (shrink)

The transcription factor Pax5 is essential for the initial commitment of hematopoietic progenitors to the B cell lineage. Recently, our understanding of the lineage commitment process has been extended with the finding that Pax5 is also continuously required throughout B cell development to reinforce commitment, as inactivation of Pax5 in mature B cells results in their de‐differentiation to a progenitor stage that is capable of multi‐lineage potential.1 The reliance of B cell identity on a single gene is not without its (...) problems as the loss of Pax5 results in B cell malignancies in mouse models and mutation in human PAX5 is the most‐common genetic lesion in acute lymphoblastic leukemia. BioEssays 30:203–207, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Over the past two decades we have seen dramatic improvements in the efficacy, safety and availibity of antiretroviral therapy (ART). In the USA and Europe, life expectancy in people living with HIV disease approaches that of the HIV-uninfected.1 Even in regions hardest hit by the HIV epidemic, effective HIV therapy has reversed more than a decade of HIV-related decreased survival. Despite these advances in ART, motivations to pursue HIV cure remain strong due to the toxicity, adherence challenges, cost and access (...) to care issues associated with HIV therapy, as well as the persistant stigma associated with having HIV infection. Further and renewed motivation comes from a single case of HIV cure after stem cell transplantation for acute leukaemia. Given the tremendous improvements in ART, it is important to assess how effective and safe an HIV cure would need to be in order to be a viable option compared to ART. We argue that this should be done prior to the availability of a cure to provide realistic goals for researchers and policy makers. One methodology that has been increasingly popular over the past decade is the use of mathematical simulation modelling to assess the clinical impact, cost-effectiveness and clinical role of different treatment strategies in HIV disease, as well as in medicine broadly.2 Such models provide a framework and approach for using the best available data at any point in time, and assessing the potential impact of emerging innovations. Further, unlike individual trials focused on a single endpoint, these models can integrate multiple data sources to project beyond the timeline or outcomes of individual studies and project long-term outcomes in many domains, including virologic, immunologic, clinical and cost.3 Mathematical models have particular value in their ability to assess uncertainty in clinical care. Examples include parameters determined in …. (shrink)

Dysregulation of genes that control cell‐cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post‐mitotic neurons under certain conditions. The gene for ataxia‐telangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss‐of‐function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (trisomy 21) (...) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss‐of‐function mutations in which account for about half of cases of early‐onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re‐expression sensitizes derivative cell lines to inhibitors of cell‐cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long‐held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders. BioEssays 30:719–727, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:A New Graduate Nurse’s StoryJill MountI was taking pre–med courses on the west coast when my mother was diagnosed with acute leukemia. I immediately finished out my classes, packed up my bags and cat and moved back to the town on the east coast where my parents lived. While my mother was fighting the leukemia, I spent many hours in her hospital room and I learned (...) more about the roles of doctors and nurses. Unlike what I had seen on television, where the doctors were always nearby and available to their patients, my mother’s doctors were seldom present. It was the nurses who spent the most time with my mother in the hospital. I wanted to care and be present for my patients like her nurses. So I decided to become a nurse. I didn’t realize that not all cancer units were like my mother’s where the nurses had time to really care for their patients.My mother’s attending doctor would visit her bedside once a day. The doctor would generally stand a few feet away from the foot of my mother’s bed and describe my mother’s latest blood counts. The doctor always seemed to keep her distance at the foot of the bed. As my mother’s series of chemotherapy treatments failed to put her in remission, the doctor would describe the next chemotherapy protocol that my mother would endure. My mother wanted desperately to live and she would keep copies of the blood counts her doctor provided her and would insist on trying the next round of chemotherapy, despite the list of grim side effects each seemed to come with. The doctor generally stayed an average of five minutes during these visits.My mother’s nurses, however, were a constant presence. I had not realized at the time that people are hospitalized primarily for nursing care. My mother was assigned several great nurses, who not only took her vital signs and administered her medications, but who seemed to care about her as a person as well. The nurses seemed to understand how difficult it was for my mother, a very independent person, not to have control over her health. To help her regain control, they provided her with guided visualizations. This was during the mid–eighties so they had her visualize her immune system as Pac–man eating all the cancer cells. My mother liked this because when she did the Pac– man visualizations, she felt she had some control directing her immune system to fight the disease.The nurses also provided my mother with emotional support. We were not a very physically affectionate family and the nurses encouraged us to give my mother hugs when she was not at risk for infections. They also gave her lots of back rubs. One of the nurses gave my mother a relaxation audiotape, which she listened to for hours, others provided her with poetry books. I believe it was partly the nurses’ physical and emotional care that enabled my mother to live as long and to fight the cancer for as long as she did. During the course of my mother’s illness, she received five rounds of chemotherapy over a period of ten months. Unfortunately her efforts to combat the cancer were unsuccessful and she died of complications of the disease and from the cumulative toxic side effects of the chemotherapy.After observing all the ways the nurses cared for my mother, I decided this was what I wanted to do and I decided to go to nursing school instead of medical school. I was able to apply my pre–med prerequisite courses to an accelerated nursing program [End Page E16] and I graduated with my bachelors in nursing after 18 months of nursing school.My nursing program emphasized the importance of viewing the patient as a whole person and not merely viewing them in terms of a particular disease or condition. Nursing school also reinforced how important nurse caring was for patients. I remember one of our exam questions focused on caring. The question was about a nurse walking into a patient’s room and finding the patient... (shrink)

The fight to find effective, long-lasting treatments for cancer has led many researchers to consider protein degrading entities. Recent developments in PROteolysis TArgeting Chimeras (PROTACs) have signified their potential as possible cancer therapies. PROTACs are small molecule, protein degraders that function by hijacking the built-in Ubiquitin-Proteasome pathway. This review mainly focuses on the general design and functioning of PROTACs as well as current advancements in the development of PROTACs as anticancer therapies. Particular emphasis is given to PROTACs designed against various (...) types of Leukemia/Blood malignancies. (shrink)

The vestibulo-ocular reflex (VOR) adaptation is an ideal model for investigating how the neurosteroid 17 beta-estradiol (E2) contributes to the modification of behavior by regulating synaptic activities. We hypothesized that E2 impacts VOR adaptation by affecting cerebellar synaptic plasticity at the parallel fiber–Purkinje cell (PF) synapse. To verify this hypothesis, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in adaptation of the VOR in male rats using an oral dose (2.5 mg/kg) of the (...) aromatase inhibitor letrozole. We also assessed the effect of letrozole on synaptic plasticity at the PF synapse in vitro, using cerebellar slices from male rats. We found that letrozole acutely impaired both gain increases and decreases adaptation of the VOR without altering basal ocular-motor performance. Moreover, letrozole prevented long-term potentiation at the PF synapse (PF-LTP) without affecting long-term depression (PF-LTD). Thus, in male rats neurosteroid E2 has a relevant impact on VOR adaptation and affects exclusively PF-LTP. These findings suggest that E2 might regulate changes in VOR adaptation by acting locally on cerebellar and extra-cerebellar synaptic plasticity sites. (shrink)

This study examined the cognitive mechanism underlying acute stress in creative cognition among individuals with high and low trait anxiety. Specifically, cognitive inhibition was assessed using the flanker task during acute stress. Fifty-two participants (26 high trait anxiety, 26 low trait anxiety) (mean age = 18.94 years) underwent stress induction via the Trier Social Stress Test (TSST). They all completed the Alternative Uses Test (AUT) and the Remote Associates Test (RAT) before and after the TSST. Biochemical markers (salivary (...) cortisol and salivary alpha amylase) were recorded at regular intervals. The results showed that cognitive inhibition was influenced by trait anxiety and acute stress. Compared to before experiencing acute stress, there was a lack of cognitive inhibition in low trait anxious individuals and they performed better in AUT (fluency) after acute stress, whereas high trait anxious individuals showed a decreased interference effect and reduced performance in AUT (fluency, flexibility, and originality). In the RAT, there were shorter response times and increased accuracy after acute stress in both high and low trait anxiety groups. Thus, we suggest that cognitive control, which modulates changes in acute stress, influences creative cognition. These findings provide evidence that inhibition control mediates the effect of stress on the creativity of individuals with different trait anxiety. (shrink)

Eyal et al have recently argued that researchers should consider conducting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human challenge studies to hasten vaccine development. We have conducted (J. L.) and overseen (L. D.) human challenge studies and agree that they can be useful in developing anti-infective agents. We also agree that adults can autonomously choose to undergo risks with no prospect of direct benefit to themselves. However, we disagree that SARS-CoV-2 challenge studies are ethically appropriate at this time, (...) for 3 reasons: (1) current scientific knowledge of SARS-CoV-2 infection is insufficient to manage risks; (2) autonomous decision making, while necessary, does not override concerns about risk; and (3) undertaking challenge studies now would imperil confidence in the research enterprise, potentially undermining the global response to the coronavirus disease 2019 (COVID-19) pandemic. (shrink)

Throughout this paper PJ Kearney attempts to balance the risks and benefits of different approaches in paediatric oncology. Decisions have to be considered both in the short and the long term. Where religious beliefs, such as those held by Jehovah's Witnesses in relation to blood transfusions, conflict with normal medical practice the decision is often removed from the doctor, parents or patient to the courts. This sort of solution can be counter-productive, especially as good health care and subsequent recovery rely, (...) to a large extent, on good relationships between and among the parties concerned. Destruction of these relationships, for whatever reason, often has a detrimental effect on the patient, in whose best interest everyone believes they are acting. (shrink)

This book showcases the best in modern medieval and religious scholarship, deploying spirited and progressive approaches to the study of Christian mysticism and the philosophy of religion. The volume explores excessive forms of desire and eroticism at play within Christian mystical texts and the historiographical, theological, and philosophical problems bound up in the interrogation of extraordinary experiences of the divine. Amy Hollywood examines how feminist and queer studies have changed the history of mysticism and how the study of religion in (...) general has altered our understanding of what is true, what is real, and what it means to research a historical subject. Ideal for novices and experienced scholars alike, this volume models cutting-edge methods for the ethical study of divine embodiment and religious experience in the Middle Ages. It makes a forceful case for thinking about religion as both belief and practice, in which traditions marked by change are passed down through generations, laying the groundwork for their own critique. Through a provocative integration of medieval sources and texts by Derrida, Butler, Asad, and Chakrabarty this book redefines what it means to engage critically with history and those embedded within it. (shrink)

How do we explain the coincidence of religion and madness in which prophets, founders of religions and great saints often show symptoms of an excitability that is extreme and even pathological? This book attempts to address this phenomenological problem. Richard Saville-Smith argues that 'acute religious experiences' provides a novel category to the study of the non-rational. This book provides an epidemiological approach to a crisis, which is non-veridical and non-reductionist, recognizing a predisposition due to gene variation as a perennial (...) constant, whilst affirming that culture contextualizes experiences. Informed by contemporary psychiatric theory, which is passed through the lens of mad studies, this book proposes the 'sweet-spot' of 'acute religious experiences' which express the phenomenality of madness – but where mad is good. This interdisciplinary study provides a species-wide account of interest to all disciplines that encounter such anomalies in their subjects, from fine art to psychiatry. (shrink)

Moral distress has been identified as an occupational hazard for clinicians caring for vulnerable populations. The aim of this systematic review was (i) to summarize the literature reporting on prevalence of, and factors related to, moral distress among nurses within acute mental health settings, and (ii) to examine the efficacy of interventions designed to address moral distress among nurses within this clinical setting. A comprehensive literature search was conducted in October 2022 utilizing Nursing & Allied Health, Embase, CINAHL, PsychInfo, (...) and PubMed databases to identify eligible studies published in English from January 2000 to October 2022. Ten studies met inclusion criteria. Four quantitative studies assessed moral distress among nurses in acute mental health settings and examined relationships between moral distress and other psychological and work-related variables. Six qualitative studies explored the phenomenon of moral distress as experienced by nurses working in acute mental health settings. The quantitative studies assessed moral distress using the Moral Distress Scale for Psychiatric Nurses (MDS-P) or the Work-Related Moral Stress Questionnaire. These studies identified relationships between moral distress and emotional exhaustion, depersonalization, cynicism, poorer job satisfaction, less sense of coherence, poorer moral climate, and less experience of moral support. Qualitative studies revealed factors associated with moral distress, including lack of action, poor conduct by colleagues, time pressures, professional, policy and legal implications, aggression, and patient safety. No interventions targeting moral distress among nurses in acute mental health settings were identified. Overall, this review identified that moral distress is prevalent among nurses working in acute mental health settings and is associated with poorer outcomes for nurses, patients, and organizations. Research is urgently needed to develop and test evidence-based interventions to address moral distress among mental health nurses and to evaluate individual and system-level intervention effects on nurses, clinical care, and patient outcomes. (shrink)

ObjectiveThe study is an explorative investigation aimed to assess the differences in acute stress response patterns of health workers facing coronavirus disease 2019 (COVID-19) during Italy’s first lockdown.MethodsA cross-sectional investigation using convenience sampling method was conducted in Italy during April 2020. Eight hundred fifty-eight health workers participated in the research filling out self-report measures including Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder (GAD-7), Insomnia Severity Index (ISI), and Impact of Event Scale–Revised (IES-R).ResultsModerate/severe depression was found in 28.9% (95% CI, (...) 25.8–32.04), moderate/severe anxiety in 55.4% (95% CI, 51.9–58.8), insomnia in 15% (95% CI, 12.5–17.5), and distress in 52.5% (95% CI, 48.5%–56.6) of participants. The 3% of health workers reported frequent suicidal thoughts. Female sex, working for >15 h/week in a COVID-19 unit, and living apart from family were associated with a significantly higher risk of distress, anxiety, insomnia, depression, and functional impairment. Four profiles were identified on the basis of psychopathological measures: Profile_0 included 44% (N= 270); Profile_1, 25.6% (N= 157); Profile_2, 19.1% (N= 117); and Profile_3, 11.3% (N= 69) of participants. Results showed a significant effect for Profiles X IES-R (η2= 0.079;f= 0.29), indicating that in all profiles, except for Profile_0, avoidance scale is lower than hyperarousal and intrusion symptoms scales of the IES-R. This characteristic could be a probable index of the control exerted by the responders to not fly away from their job.ConclusionThe identification of specific profiles could help psychiatrists and emergency psychologists to build specific interventions in terms of both primary and secondary prevention to face future waves of the COVID-19 outbreak. (shrink)

Acute aerobic exercise has been shown to improve fine motor skills and alter activation of the motor cortex. The intensity of exercise may influence M1 activation, and further impact whole-body motor skill performance. The aims of the current study were to compare a whole-body motor skill via a piano task following moderate-intensity training and high-intensity interval training, and to determine if M1 activation is linked to any such changes in performance. Nine subjects, aged 18 ± 1 years completed a (...) control, MIT, and HIIT trial followed by administration of a piano performance task. M1 activation was evaluated by measuring oxyhemoglobin and hemoglobin difference changes during post-exercise piano performance using functional near-infrared spectroscopy. The results indicate that piano performance scores were higher after the MIT trial, but not HIIT trial, compared to the control trial. A negative relationship was detected between heart rate during HIIT and post-HIIT piano scores. M1 activation was significantly increased after the HIIT trial. M1 activation was also positively associated with piano performance when exercise trials and all trials were combined. We found that acute moderate-intensity exercise led to an improvement in complex motor skill performance while higher-intensity exercise increased M1 activation. These results demonstrate that moderate-intensity exercise can prime the nervous system for the acquisition of whole-body motor skills, suggesting that similar exercise protocols may be effective in improving the outcomes of other motor tasks performed during regular routines of daily life. In addition, it appears that improvements in motor task performance may be driven by M1 activation. Our findings provide new mechanistic insight into the complex relationship between exercise intensity, M1 activation, and whole-body motor skill performance. (shrink)