Patients with chronic lymphocytic leukemia (CLL) with high-risk genomic features achieve poor outcomes with traditional therapies. A phase I study of a pharmacokinetically derived schedule of ...flavopiridol suggested promising activity in CLL, irrespective of high-risk features. Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated.
Patients with relapsed CLL were treated with single-agent flavopiridol, with subsequent addition of dexamethasone to suppress cytokine release syndrome (CRS). High-risk genomic features were prospectively assessed for response to therapy.
Sixty-four patients were enrolled. Median age was 60 years, median number of prior therapies was four, and all patients had received prior purine analog therapy. If patients tolerated treatment during week 1, dose escalation occurred during week 2. Dose escalation did not occur in four patients, as a result of severe tumor lysis syndrome; three of these patients required hemodialysis. Thirty-four patients (53%) achieved response, including 30 partial responses (PRs; 47%), three nodular PRs (5%), and one complete response (1.6%). A majority of high-risk patients responded; 12 (57%) of 21 patients with del(17p13.1) and 14 (50%) of 28 patients with del(11q22.3) responded irrespective of lymph node size. Median progression-free survival among responders was 10 to 12 months across all cytogenetic risk groups. Reducing the number of weekly treatments per cycle from four to three and adding prophylactic dexamethasone, which abrogated interleukin-6 release and CRS (P < or = .01), resulted in improved tolerability and treatment delivery.
Flavopiridol achieves significant clinical activity in patients with relapsed CLL, including those with high-risk genomic features and bulky lymphadenopathy. Subsequent clinical trials should use the amended treatment schedule developed herein and prophylactic corticosteroids.
Targeted therapy with imatinib in chronic myeloid leukemia (CML) prompted a new treatment paradigm. Unlike CML, chronic lymphocytic leukemia (CLL) lacks an aberrant fusion protein kinase but instead ...displays increased phosphatidylinositol 3-kinase (PI3K) activity. To date, PI3K inhibitor development has been limited because of the requirement of this pathway for many essential cellular functions. Identification of the hematopoietic-selective isoform PI3K-δ unlocks a new therapeutic potential for B-cell malignancies. Herein, we demonstrate that PI3K has increased enzymatic activity and that PI3K-δ is expressed in CLL cells. A PI3K-δ selective inhibitor CAL-101 promoted apoptosis in primary CLL cells ex vivo in a dose- and time-dependent fashion that was independent of common prognostic markers. CAL-101–mediated cytotoxicity was caspase dependent and was not diminished by coculture on stromal cells. In addition, CAL-101 abrogated protection from spontaneous apoptosis induced by B cell–activating factors CD40L, TNF-α, and fibronectin. In contrast to malignant cells, CAL-101 does not promote apoptosis in normal T cells or natural killer cells, nor does it diminish antibody-dependent cellular cytotoxicity. However, CAL-101 did decrease activated T-cell production of various inflammatory and antiapoptotic cytokines. Collectively, these studies provide rationale for the clinical development of CAL-101 as a first-in-class targeted therapy for CLL and related B-cell lymphoproliferative disorders.
Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in ...XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Of the remaining cohort, two probands had no variants and six probands had only a single variant, including four with a heterozygous 3.1 Mb 16p13 deletion encompassing XYLT1 and two with a heterozygous truncating variant. Bisulfite sequencing revealed aberrant hypermethylation in exon 1 of XYLT1, always in trans with the sequence variant or deletion when present; both alleles were methylated in those with no identified variant. Expression of the methylated XYLT1 allele was severely reduced in fibroblasts from two probands. Southern blot studies combined with repeat expansion analysis of genome sequence data showed that the hypermethylation is associated with expansion of a GGC repeat in the XYLT1 promoter region that is not present in the reference genome, confirming that BSS is a trinucleotide repeat expansion disorder. The hypermethylated allele accounts for 50% of disease alleles in our cohort and is not present in 130 control subjects. Our study highlights the importance of investigating non-sequence-based alterations, including epigenetic changes, to identify the missing heritability in genetic disorders.
Pediatric patients rarely present with severe, complicated Clostridium difficile colitis. The medical and surgical management of pediatric patients is primarily based on evidence from adult ...populations, in which standard therapy often includes subtotal colectomy and end ileostomy. New evidence in adults suggests that a diverting loop ileostomy and colonic lavage is an effective alternative for the management of refractory severe, complicated C difficile colitis. We report the case of a 15-year-old female patient who developed severe, complicated C difficile colitis. After failing medical management, she underwent a diverting loop ileostomy with antegrade colonic lavage and recovered uneventfully. There is limited literature on the medical management of C difficile–associated disease in pediatric patients and even less information on the medical or surgical management of severe, complicated C difficile colitis in pediatrics. Diverting loop ileostomy and colonic lavage should be considered as an alternative to subtotal colectomy and end ileostomy in a pediatric patient with severe, complicated C difficile colitis.
Ex utero intrapartum treatment (EXIT) procedures Bence, Christina M.; Wagner, Amy J.
Seminars in pediatric surgery,
August 2019, 2019-Aug, 2019-08-00, 20190801, Letnik:
28, Številka:
4
Journal Article
Recenzirano
Ex Utero Intrapartum Treatment (EXIT) is a technique developed to safely and efficiently establish cardiopulmonary support at delivery while maintaining placental bypass. Indications for the EXIT ...approach are expanding and currently include EXIT-to-airway, EXIT-to-resection, EXIT-to-extracorporeal membrane oxygenation (ECMO), and EXIT-to-separation of conjoined twins. The EXIT technique involves planned partial delivery of the fetus via hysterotomy while maintaining uterine relaxation and placental support, allowing for the establishment of neonatal cardiopulmonary stability in a controlled manner. Fetal interventions performed during EXIT can include endotracheal intubation, tracheostomy, mass excision, removal of a temporary tracheal occlusive device, ECMO cannulation, and others. The most important aspect of an EXIT procedure is the formation of a multi-disciplinary team with broad expertise in fetal intervention to collaborate throughout the pre, intra, and post-partum periods. This chapter reviews the prenatal workup, decision making, surgical indications, and operative considerations associated with EXIT procedures.
Pokémon GO: Healthy or Harmful? Wagner-Greene, Victoria R; Wotring, Amy J; Castor, Thomas ...
American journal of public health
107, Številka:
1
Journal Article
Cyclin dependent kinase (CDK) inhibitors, such as flavopiridol, demonstrate significant single-agent activity in chronic lymphocytic leukemia (CLL), but the mechanism of action in these ...nonproliferating cells is unclear. Here we demonstrate that CLL cells undergo autophagy after treatment with therapeutic agents, including fludarabine, CAL-101, and flavopiridol as well as the endoplasmic reticulum (ER) stress-inducing agent thapsigargin. The addition of chloroquine or siRNA against autophagy components enhanced the cytotoxic effects of flavopiridol and thapsigargin, but not the other agents. Similar to thapsigargin, flavopiridol robustly induces a distinct pattern of ER stress in CLL cells that contributes to cell death through IRE1-mediated activation of ASK1 and possibly downstream caspases. Both autophagy and ER stress were documented in tumor cells from CLL patients receiving flavopiridol. Thus, CLL cells undergo autophagy after multiple stimuli, including therapeutic agents, but only with ER stress mediators and CDK inhibitors is autophagy a mechanism of resistance to cell death. These findings collectively demonstrate, for the first time, a novel mechanism of action (ER stress) and drug resistance (autophagy) for CDK inhibitors, such as flavopiridol in CLL, and provide avenues for new therapeutic combination approaches in this disease.
Elective preterm delivery (EPD) of a fetus with gastroschisis may prevent demise and ameliorate intestinal injury. While the literature on optimal timing of delivery varies, we hypothesize that a ...potential benefit may be found with EPD.
A meta-analysis of publications describing timing of delivery in gastroschisis from 1/1990 to 8/2016 was performed, including studies where either elective preterm delivery (group 1, G1) or preterm gestational age (GA) (group 2, G2) were evaluated against respective comparators. The following outcomes were analyzed: total parenteral nutrition (TPN), first enteral feeding (FF), length of stay, ventilator days, fetal demise, complex gastroschisis, sepsis, and death.
Eighteen studies describing 1430 gastroschisis patients were identified. G1 studies found less sepsis (p<0.01), fewer days to FF (p=0.03), and 11days less of TPN (p=0.07) in the preterm cohort. Comparatively, G2 studies showed less days to FF in term GA (p=0.02).Whereas G1 BWs were similar, G2 preterm had a significantly lower BW compared to controls (p=0.001).
Elective preterm delivery appears favorable with respect to feeding and sepsis. However, benefits are lost when age is used as a surrogate of EPD. A randomized, prospective, multi-institutional trial is necessary to delineate whether EPD is advantageous to neonates with gastroschisis.
Treatment study.
Level III.
Plague is a pandemic human invasive disease caused by the bacterial agent Yersinia pestis. We here report a comparison of 17 whole genomes of Y. pestis isolates from global sources. We also screened ...a global collection of 286 Y. pestis isolates for 933 SNPs using Sequenom MassArray SNP typing. We conducted phylogenetic analyses on this sequence variation dataset, assigned isolates to populations based on maximum parsimony and, from these results, made inferences regarding historical transmission routes. Our phylogenetic analysis suggests that Y. pestis evolved in or near China and spread through multiple radiations to Europe, South America, Africa and Southeast Asia, leading to country-specific lineages that can be traced by lineage-specific SNPs. All 626 current isolates from the United States reflect one radiation, and 82 isolates from Madagascar represent a second radiation. Subsequent local microevolution of Y. pestis is marked by sequential, geographically specific SNPs.
The decrease in δ13C of dissolved inorganic carbon (δ13CDIC) owing to uptake of anthropogenic CO2 (the oceanic 13C Suess effect) in the Southeastern Indian Ocean over the last decade was calculated ...using an extended multiparameter linear regression technique. Samples collected on the CROCCA‐2S (Coring to Reconstruct Ocean Circulation and Carbon Dioxide Across 2 Seas) cruise in November–December 2018 were compared to samples from the CLIVAR (Climate and Ocean: Variability, Predictability, and Change) and OISO (Océan Indien Service d'Observation) programs from 2007 to 2009. Surface ocean δ13CDIC decreased by an average of −0.53 ± 0.04‰ across this period, at an average rate of −0.053 ± 0.004‰ per year. This rate of δ13CDIC change is an increase from −0.021 ± 0.024‰ per year between 1994 and 2008. We find that the interior water mass most impacted by the oceanic 13C Suess effect between 2008 and 2018 was Subantarctic Mode Water (SAMW), within which δ13CDIC decreased by −0.044 ± 0.002‰ per year. Using previously published relationships between the oceanic 13C Suess effect and anthropogenic carbon, we estimate the annual storage of anthropogenic carbon within SAMW in the southeastern Indian Ocean has increased from ∼2.0 ± 0.2 μmol/kg per year between 1994 and 2008 to 5.5 ± 0.6 μmol/kg per year between 2008 and 2018.
Plain Language Summary
We measured the ratio of carbon isotopes within seawater to identify the amount of atmospheric carbon sourced from the burning of biomass and fossil fuels which has been absorbed into the southeastern Indian Ocean over the last decade. We find that the rate at which this human‐sourced carbon is being absorbed by the ocean has increased up to 3‐fold over this time period, when compared with the period between 1994 and 2008.
Key Points
The oceanic Suess effect disproportionately affects Subantarctic Mode Water (SAMW), within which δ13C has decreased by c. −0.44‰ from 2008 to 2018
The observed δ13C change of −0.044‰/year represents roughly a 3‐fold increase in the rate of δ13C change compared to 1994–2008
Between 2008 and 2018 SAMW in the SE Indian Ocean absorbed 5.5 ± 0.6 μmol/kg−1 of anthropogenic carbon per year
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