Anticoagulation Strategies in Patients With Cancer: JACC Review Topic of the Week

Patients with active cancer are at an increased risk of arterial and venous thromboembolism (VTE) and bleeding events. Historically, in patients with cancer, low molecular weight heparins have been preferred for treatment of VTE, whereas warfarin has been the standard anticoagulant for stroke prevention in patients with atrial fibrillation (AF). More recently, direct oral anticoagulants (DOACs) have been demonstrated to reduce the risk of venous and arterial thromboembolism in large randomized clinical trials of patients with VTE and AF, respectively, thus providing an attractive oral dosing option that does not require routine laboratory monitoring. In this review, we summarize available clinical trial data and guideline recommendations, and outline a practical approach to anticoagulation management of VTE and AF in cancer.     

Evaluation of the PROMIS pediatric global health scale (PGH-7) in children with asthma

Objective: To evaluate the reliability and validity of the PROMIS Pediatric Global Health scale, a 7-item measure of perceived physical, mental, and social health, in children with asthma. Methods: From February 2014 to February 2015, convenience samples of 8–17 year-old children (n = 182) and parents of 5–17 year-old children (n = 328) visiting an emergency department for treatment of asthma were enrolled. The Asthma Control Test was used to characterize children as controlled versus not controlled, and the PROMIS Asthma Impact Scale was used to assess asthma symptoms' impact on functional status. We conducted longitudinal analyses among 92 children and 218 parents at 3 weeks, and 74 children and 171 parents at 8 weeks after enrollment. Results: The PGH-7 reliability ranged from 0.66 to 0.81 for child-report and 0.76 to 0.82 for parent-proxy. In cross-sectional analyses, children with controlled asthma had PGH-7 scores 0.40–0.95 standard deviation units higher than those who were uncontrolled. The PGH-7 was responsive to changes in overall general health between time points, with moderate effect sizes (0.5–0.6 standard deviation units). In longitudinal analyses, PGH-7 scores were no different between those who stayed uncontrolled versus became controlled at 3 weeks of follow-up; however, by 8 weeks of follow-up, the differences between these groups were 0.7–0.8 standard deviation units, indicative of large effects. Conclusions: The PGH-7 is a reliable and valid patient-reported outcome for assessing general health among children with asthma. It is a useful complement to other asthma-specific outcome measures.     

Relative Prevalence and Outcome of Fetal Neural Tube Defect in a Developing Country

Objectives

To find out the relative prevalence of fetal neural tube defect (NTD) and its outcome in terms of survival at birth and beyond 2 years of age.

Methods

A 10-year prospective (2008–2018) observational study was performed, which included all prenatally detected fetal NTD. Two-year follow-up was done in cases of pregnancies resulting in live birth, in terms of their survival, physical morbidity and developmental delay.

Results

NTD was seen in 401/648 (62%) cases among the central nervous system malformations. More than half of the cases (54.1%) presented after 20 weeks of gestation, and 42.8% of the mothers were primiparous. Spina bifida was seen in 206 cases, anencephaly in 144, encephalocele in 43, whereas iniencephaly was seen in only eight cases. Associated anomalies were present in 51.2%. Only 19.0% cases were live-born, and merely 11% were alive beyond 2 years of age. Among types of spina bifida, lumbosacral meningomyocele was the most common (41.6%), whereas thoracic was the rarest (8.7%). After 2 years, physical disability was observed in more than half of the cases who survived.

Conclusions

NTD is one of the commonest malformations with high mortality, and the physical and mental sub-normality is high among those who survive.

     

Ancient dynamin segments capture early stages of host–mitochondrial integration

Eukaryotic cells use dynamins—mechano-chemical GTPases—to drive the division of endosymbiotic organelles. Here we probe early steps of mitochondrial and chloroplast endosymbiosis by tracing the evolution of dynamins. We develop a parsimony-based phylogenetic method for protein sequence reconstruction, with deep time resolution. Using this, we demonstrate that dynamins diversify through the punctuated transformation of sequence segments on the scale of secondary-structural elements. We find examples of segments that have remained essentially unchanged from the 1.8-billion-y-old last eukaryotic common ancestor to the present day. Stitching these together, we reconstruct three ancestral dynamins: The first is nearly identical to the ubiquitous mitochondrial division dynamins of extant eukaryotes, the second is partially preserved in the myxovirus-resistance-like dynamins of metazoans, and the third gives rise to the cytokinetic dynamins of amoebozoans and plants and to chloroplast division dynamins. The reconstructed sequences, combined with evolutionary models and published functional data, suggest that the ancestral mitochondrial division dynamin also mediated vesicle scission. This bifunctional protein duplicated into specialized mitochondrial and vesicle variants at least three independent times—in alveolates, green algae, and the ancestor of fungi and metazoans—accompanied by the loss of the ancient prokaryotic mitochondrial division protein FtsZ. Remarkably, many extant species that retain FtsZ also retain the predicted ancestral bifunctional dynamin. The mitochondrial division apparatus of such organisms, including amoebozoans, red algae, and stramenopiles, seems preserved in a near-primordial form.Eukaryotes arose through the acquisition of mitochondria by an archaeal host cell about 2 billion y ago (1, 2), a watershed moment in the evolution of the modern compartmentalized cell plan (3). A second transformative endosymbiotic event, the acquisition of a cyanobacterium by a eukaryotic host to form chloroplasts, gave rise to the photosynthetic eukaryotic lineages (4). As the endosymbionts became integrated with their hosts, their growth and division became regulated by host–cellular machinery (5). Proteins of the dynamin superfamily were central to this process: Mitochondria and chloroplasts originally divided using a constricting ring of the prokaryotic cytoskeletal protein FtsZ, but dynamins have been recruited to these roles in all extant eukaryotes (6, 7). By reconstructing the evolutionary history of dynamins, we can probe the process of endosymbiont integration.The dynamin superfamily is diverse (8, 9), and different dynamin variants remodel membranes at different cellular locations (Table S1 and primary references therein). A major class of dynamins is essential for mitochondrial and peroxisomal division. Another large group drives the scission of clathrin-coated vesicles in organisms such as fungi and alveolates. A related group, the so-called “classical” dynamins that drive clathrin-coated vesicle scission in metazoans and land plants, contains a membrane-targeted pleckstrin homology (PH) domain. Members of the phragmoplastin class of dynamins participate in cell plate formation in land plants. The myxovirus-resistance-like dynamins are implicated in antiviral activity in vertebrates. A truncated dynamin variant is involved in cytokinesis in amoebozoans and plants, as well as in chloroplast fission in photosynthetic lineages; another truncated variant drives mitochondrial inner membrane fusion in fungi and metazoans. Finally, mitofusins and the related bacterial dynamin-like proteins (BDLPs) are potentially ancient members of the dynamin superfamily (10); these are excluded from our study because they are highly diverged at the sequence level.Here we present the most comprehensive analysis of dynamin evolution yet reported, including thousands of functionally diverse dynamins from hundreds of broadly sampled eukaryotic species. We reconstruct the series of events that led from the primordial dynamins of the 1.8-billion-y-old last eukaryotic common ancestor (LECA) (11) to the great variety of present-day dynamins. The outcome is a nuanced picture of protein diversification, mirroring key events in the evolution of eukaryotes themselves and shedding light on the earliest stages of endosymbiont integration.     

A Randomized Clinical Trial of Levonorgestrel Intrauterine System with or without Metformin for Treatment of Endometrial Hyperplasia without Atypia in Indian Women

Background: Endometrial cancer is the second most frequent genital malignancy in women, which is showing a constant rise all over world. Endometrial hyperplasia is the precursor of endometrial cancer. Levonorgestrel intrauterine system is the first line management in patients with endometrial hyperplasia without atypia. Metformin has shown to reverse endometrial hyperplasia, but its effectiveness and safety in endometrial hyperplasia is uncertain. Objective: To compare the efficacy in terms of histopathological response, clinical response and safety at the end of 6 months in patients with endometrial hyperplasia without atypia managed with levonorgestrel intrauterine system alone versus patients managed with levonorgestrel intrauterine system plus metformin. Methods: The randomized control trial was conducted on 51 cases of endometrial hyperplasia without atypia. Twenty-five subjects were prescribed metformin 500mg twice daily with levonorgestrel intrauterine system and 26 subjects, with levonorgestrel intrauterine system only for 6 months. At the end of 6 months, endometrial sampling was performed for histopathological response. Results: Clinical response was observed in 23 of 25 subjects in metformin group and 22 of 24 in levonorgestrel only group. The metformin group responded significantly with amenorrhea (p= 0.0053), while levonorgestrel only group responded with regular cycles (p=0.027). At the end of study, of 46 subjects available for histopathological evaluation, 100% subjects in metformin group and 95.45% in levonorgestrel only group (p=0.47826) showed complete response. The metformin group had a significant reduction in body mass index at end of study [P = 0∙023, 95% confidence interval (-1.7802, -0.1418)]. Conclusion: No significant difference in regression of endometrial hyperplasia was observed on adjunctive use of metformin but a significant reduction in BMI was observed. Use of metformin in obese patients may improve the treatment response.     

The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice

Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid beta (Abeta) accumulation, extracellular Abeta deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD.     

p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia

MYC-induced T-ALL exhibit oncogene addiction. Addiction to MYC is a consequence of both cell-autonomous mechanisms, such as proliferative arrest, cellular senescence, and apoptosis, as well as non-cell autonomous mechanisms, such as shutdown of angiogenesis, and recruitment of immune effectors. Here, we show, using transgenic mouse models of MYC-induced T-ALL, that the loss of either p19ARF or p53 abrogates the ability of MYC inactivation to induce sustained tumor regression. Loss of p53 or p19ARF, influenced the ability of MYC inactivation to elicit the shutdown of angiogenesis; however the loss of p19ARF, but not p53, impeded cellular senescence, as measured by SA-beta-galactosidase staining, increased expression of p16INK4A, and specific histone modifications. Moreover, comparative gene expression analysis suggested that a multitude of genes involved in the innate immune response were expressed in p19ARF wild-type, but not null, tumors upon MYC inactivation. Indeed, the loss of p19ARF, but not p53, impeded the in situ recruitment of macrophages to the tumor microenvironment. Finally, p19ARF null-associated gene signature prognosticated relapse-free survival in human patients with ALL. Therefore, p19ARF appears to be important to regulating cellular senescence and innate immune response that may contribute to the therapeutic response of ALL.     

Iron Deficiency Anemia Associated With Acid-Modifying Medications: Two Cases and Literature Review

Iron deficiency anemia is often listed among potential adverse effects of gastric acid-suppressive medications, given that gastric acidity promotes intestinal absorption of nonheme iron. Additionally, the antacid calcium carbonate can inhibit iron absorption. However, there is little direct clinical evidence that proton-pump inhibitors, histamine-2 receptor antagonists, or calcium carbonate cause iron deficiency anemia. Most case reports have had substantial limitations (e.g., minimal follow-up and presence of other causes of iron deficiency), and retrospective cohort studies have lacked sufficient patient-specific detail to make strong causal inferences. We present 2 cases—both with detailed, prospective 10-year follow-up—in which combinations of proton-pump inhibitors, histamine-2 receptor antagonists and calcium carbonate were clearly associated with development of iron deficiency anemia. Overt iron-deficiency anemia is probably uncommon in patients who use acid-modifying medications and who have no other conditions that predispose to iron deficiency. Nevertheless, clinicians should be aware of this potential complication, given widespread use of these agents.