Background
An objective of the phase 3 HELP Study was to investigate the effect of lanadelumab on health‐related quality of life (HRQoL) in patients with hereditary angioedema (HAE).
Methods
Patients ...with HAE‐1/2 received either lanadelumab 150 mg every 4 weeks (q4wks; n = 28), 300 mg q4wks (n = 29), 300 mg every 2 weeks (q2wks; n = 27), or placebo (n = 41) for 26 weeks (days 0–182). The Angioedema Quality of Life Questionnaire (AE‐QoL) was administered monthly, consisting of four domain (functioning, fatigue/mood, fears/shame, nutrition) and total scores. The generic EQ‐5D‐5L questionnaire was administered on days 0, 98, and 182. Comparisons were made between placebo and (a) all lanadelumab‐treated patients and (b) individual lanadelumab groups for changes in scores (day 0–182) and proportions achieving the minimal clinically important difference (MCID, −6) in AE‐QoL total score.
Results
Compared with the placebo group, the lanadelumab total group demonstrated significantly greater improvements in AE‐QoL total and domain scores (mean change, −13.0 to −29.3; p < 0.05 for all); the largest improvement was in functioning. A significantly greater proportion of the lanadelumab total group achieved the MCID (70% vs 37%; p = 0.001). The lanadelumab 300 mg q2wks group had the highest proportion (81%; p = 0.001) and was 7.2 times more likely to achieve the MCID than the placebo group. Mean EQ‐5D‐5L scores at day 0 were high in all groups, indicating low impairment, with no significant changes at day 182.
Conclusion
Patients with HAE‐1/2 experienced significant and clinically meaningful improvements in HRQoL measured by AE‐QoL following lanadelumab treatment in the HELP Study.
In the phase 3 HELP Study, HRQoL (health‐related quality of life) of patients with HAE (hereditary angioedema)‐1/2 was evaluated using the angioedema‐specific AE‐QoL (Angioedema Quality of Life Questionnaire). After 26 weeks, lanadelumab‐treated patients experienced significantly greater HRQoL improvements than placebo‐treated patients. Patients receiving lanadelumab 300 mg q2wks (every 2 weeks) were most likely to see clinically meaningful benefit, with 81% reaching the MCID (minimal clinically important difference) and seven times greater odds vs placebo for this achievement.
Abbreviations: AE‐QoL, Angioedema Quality of Life Questionnaire; HAE, hereditary angioedema; HRQoL, health‐related quality of life; MCID, minimal clinically important difference; q2wks, every 2 weeks; q4wks, every 4 weeks.
In metazoans, tissues experiencing proteotoxic stress induce “transcellular chaperone signaling” (TCS) that activates molecular chaperones, such as hsp-90, in distal tissues. How this form of ...inter-tissue communication is mediated to upregulate systemic chaperone expression and whether it can be utilized to protect against protein misfolding diseases remain open questions. Using C. elegans, we identified key components of a systemic stress signaling pathway that links the innate immune response with proteostasis maintenance. We show that mild perturbation of proteostasis in the neurons or the intestine activates TCS via the GATA zinc-finger transcription factor PQM-1. PQM-1 coordinates neuron-activated TCS via the innate immunity-associated transmembrane protein CLEC-41, whereas intestine-activated TCS depends on the aspartic protease ASP-12. Both TCS pathways can induce hsp-90 in muscle cells and facilitate amelioration of Aβ3-42-associated toxicity. This may have powerful implications for the treatment of diseases related to proteostasis dysfunction.
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•PQM-1 is activated in the neurons or gut to induce TCS-mediated hsp-90 expression•Neuron-induced TCS is mediated via PQM-1/CLEC-41 signaling•Intestine-induced TCS is mediated via PQM-1/ASP-12 signaling•TCS via PQM-1 is required for proteostasis and reduces amyloid beta misfolding
O’Brien et al. find that the GATA transcription factor PQM-1 functions as a mediator of transcellular chaperone signaling (TCS). Depending on the sender tissue, PQM-1 activates a neuron-specific or intestine-specific TCS route that triggers hsp-90 expression in remote tissues. TCS-mediated hsp-90 induction reduces amyloid beta oligomerization and toxicity.
An experiment was conducted to determine if dietary Yucca-derived saponin supplementation could ameliorate the immune and growth responses of broilers during a mixed coccidian challenge. A total of ...576 two-day-old male Ross 308 broiler chicks were housed in galvanized starter batteries and randomly assigned to 1 of 4 dietary treatment groups (12 replicate cages of 12 birds). Dietary treatments were corn-soybean meal-based and included 1) control diet + sham-inoculated (Ucon), 2) control diet + Eimeria oocyst challenge (Icon), 3) control diet with 250 mg/kg Yucca-derived saponin product + Eimeria oocyst challenge (ISap250), and 4) control diet with 500 mg/kg of Yucca-derived saponin product + Eimeria oocyst challenge (ISap500). On study day 14, birds were orally inoculated with 1.5 mL of tap water containing Eimeria acervulina, E. maxima, and E. tenella (100,000, 40,000, and 30,000 oocysts/dose, respectively), or sham-inoculated with 1.5 mL of tap water. Eimeria-challenged birds exhibited a reduction in growth compared with uninfected birds (P < 0.001); however, there were no detectable differences due to dietary treatment among Eimeria-challenged groups. Mucosal thickness in the jejunum was increased (P < 0.042) in all infected groups and there were no differences among infected groups; however, saponin supplementation included at 250 mg/kg was not significantly different from the uninfected birds. Lymphocytes as a percentage of total white blood cells were increased (P < 0.014) in all Eimeria-challenged groups at 7 D post-inoculation compared with uninfected birds, but birds supplemented at 250 mg/kg were not different from uninfected birds. Cecal and duodenal IFN-γ expression increased with infection when compared with sham-inoculated birds. Cecal and duodenal IL-1β expression increased (P < 0.008 and P < 0.039) due to infection, and ISap250 and ISap500 treatments ameliorated IL-1β expression to levels not different from sham-inoculated birds. These results suggest that saponin supplementation may provide some immunomodulatory effects during a mixed coccidian challenge as evidenced by lymphocyte responses, changes in intestinal structure, and alterations in cecal and duodenal inflammatory cytokine mRNA expression.
Abstract Objective To compare the effectiveness of self-collected and health care worker (HCW)–collected nasal swabs for detection of influenza viruses and determine the patients' preference for type ...of collection. Patients and Methods We enrolled adult patients presenting with influenzalike illness to the Emergency Department at Mayo Clinic, Rochester, Minnesota, from January 28, 2011, through April 30, 2011. Patients self-collected a midturbinate nasal flocked swab from their right nostril following written instructions. A second swab was then collected by an HCW from the left nostril. Swabs were tested for influenza A and B viruses by real-time reverse transcription–polymerase chain reaction, and percent concordance between collection methods was determined. Results Of the 72 paired specimens analyzed, 25 were positive for influenza A or B RNA by at least one of the collection methods (34.7% positivity rate). When the 14 patients who had prior health care training were excluded, the qualitative agreement between collection methods was 94.8% (55 of 58). Two of the 58 specimens (3.4%) from patients without health care training were positive only by HCW collection, and 1 of 58 (1.7%) was positive only by patient self-collection. A total of 53.4% of patients (31 of 58) preferred the self-collection method over the HCW collection, and 25.9% (15 of 58) had no preference. Conclusion Self-collected midturbinate nasal swabs provide a reliable alternative to HCW collection for influenza A and B virus real-time reverse transcription–polymerase chain reaction.
The experience of pain arises from both physiological and psychological factors, including one's beliefs and expectations. Thus, placebo treatments that have no intrinsic pharmacological effects may ...produce analgesia by altering expectations. However, controversy exists regarding whether placebos alter sensory pain transmission, pain affect, or simply produce compliance with the suggestions of investigators. In two functional magnetic resonance imaging (fMRI) experiments, we found that placebo analgesia was related to decreased brain activity in pain-sensitive brain regions, including the thalamus, insula, and anterior cingulate cortex, and was associated with increased activity during anticipation of pain in the prefrontal cortex, providing evidence that placebos alter the experience of pain.
The assembly of semiconductor nanowires and carbon nanotubes into nanoscale devices and circuits could enable diverse applications in nanoelectronics and photonics. Individual semiconducting ...nanowires have already been configured as field-effect transistors, photodetectors and bio/chemical sensors. More sophisticated light-emitting diodes (LEDs) and complementary and diode logic devices have been realized using both n- and p-type semiconducting nanowires or nanotubes. The n- and p-type materials have been incorporated in these latter devices either by crossing p- and n-type nanowires or by lithographically defining distinct p- and n-type regions in nanotubes, although both strategies limit device complexity. In the planar semiconductor industry, intricate n- and p-type and more generally compositionally modulated (that is, superlattice) structures are used to enable versatile electronic and photonic functions. Here we demonstrate the synthesis of semiconductor nanowire superlattices from group III-V and group IV materials. (The superlattices are created within the nanowires by repeated modulation of the vapour-phase semiconductor reactants during growth of the wires.) Compositionally modulated superlattices consisting of 2 to 21 layers of GaAs and GaP have been prepared. Furthermore, n-Si/p-Si and n-InP/p-InP modulation doped nanowires have been synthesized. Single-nanowire photoluminescence, electrical transport and electroluminescence measurements show the unique photonic and electronic properties of these nanowire superlattices, and suggest potential applications ranging from nano-barcodes to polarized nanoscale LEDs.
Summary
Background
Inorganic polyphosphate (polyP) elicits pro‐inflammatory signaling responses in endothelial cells through interaction with two receptors, RAGE and P2Y1. It is known that polyP ...activates mTOR signaling in breast cancer cells.
Objectives
The objective of this study is to understand the mechanism of the polyP‐mediated signaling pathway in endothelial cells and to determine whether polyP exerts its pro‐inflammatory effect through activation of mTOR.
Methods
mTOR activation by polyP or platelet releasates in cellular and animal models was monitored in the absence and presence of pharmacological inhibitors and/or siRNA knockdown of specific signaling molecules.
Results
PolyP effectively induced phosphorylation of mTOR complex 1 (mTORC1) substrate, p70S6K, in endothelial cells by an AKT‐dependent but ERK‐independent mechanism. The siRNA knockdown of both RAGE and P2Y1 or specific inhibitors of the PI3K/PLC/PKC/Ca2+ signaling axis inhibited polyP‐mediated p70S6K phosphorylation. Moreover, either rapamycin or siRNA knockdown of raptor (mTORC1‐specific component) abrogated polyP‐mediated phosphorylation of p70S6K. By contrast, the siRNA knockdown of rictor (mTOR complex 2‐specific component) but not raptor eliminated the barrier‐disruptive effect of polyP. Specific NF‐κB inhibitors abrogated polyP‐mediated phosphorylation of p70S6K and rapamycin suppressed polyP‐induced activation of NF‐κB. Finally, specific inhibitors of the mTOR signaling network eliminated polyP‐mediated vascular leakage and leukocyte recruitment in animal models.
Conclusions
PolyP, through interaction with RAGE and P2Y1, activates both the mTORC1 and mTORC2 signaling network. Both the pro‐inflammatory and mTOR signaling functions of polyP are linked.
Objective Autism spectrum disorder (ASD) is associated with preterm birth (PTB), although the reason underlying this relationship is still unclear. Our objective was to examine DNA methylation ...patterns of 4 ASD candidate genes in human fetal membranes from spontaneous PTB and uncomplicated term birth. Study Design A literature search for genes that have been implicated in ASD yielded 14 candidate genes ( OXTR , SHANK3 , BCL2 , RORA , EN2 , RELN , MECP2, AUTS2, NLGN3, NRXN1, SLC6A4, UBE3A, GABA, AFF2 ) that were epigenetically modified in relation to ASD. DNA methylation in fetal leukocyte DNA in 4 of these genes ( OXTR , SHANK3 , BCL2 , and RORA ) was associated with PTB in a previous study. This study evaluated DNA methylation, transcription (reverse transcription polymerase chain reaction), and translation patterns (immunostaining and Western blot) in fetal membrane from term labor (n = 14), term not in labor (TNIL; n = 29), and spontaneous preterm birth (PTB; n = 27). Statistical analysis was performed with analysis of variance; a probability value of < .05 was significant. Results Higher methylation of the OXTR promoter was seen in fetal membranes from PTB, compared with term labor or TNIL. No other gene showed any methylation differences among groups. Expression of OXTR was not different among groups, but the 70 kDa OXTR protein was seen only in PTB, and immunostaining was more intense in PTB amniocytes than term labor or TNIL. Conclusion Among the 4 genes that were studied, fetal membranes from PTB demonstrate differences in OXTR methylation and regulation and expression, which suggest that epigenetic alteration of this gene in fetal membrane may likely be indicating an in utero programing of this gene and serve as a surrogate in a subset of PTB. The usefulness of OXTR hypermethylation as a surrogate for a link to ASD should be further evaluated in longitudinal and in vitro studies.
Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding ...patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses.
In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes overall survival (OS) and progression-free survival (PFS) among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone.
Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS.
Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.
•Treatment of concomitant melanoma with ICI resulted in durable clinical responses despite concomitant CLL.•The ORR to first-line ICI was 41% and median duration of response was 18 months.•Prior treatment for CLL was associated with poor ICI-dependent outcomes, including ORRs, OS, and PFS.•Clinical benefit was achieved without exacerbation of CLL or clearly increased adverse event rates.
Context.
The sub-Jovian, or Neptunian, desert is a previously identified region of parameter space where there is a relative dearth of intermediate-mass planets with short orbital periods.
Aims.
We ...present the discovery of a new transiting planetary system within the Neptunian desert, NGTS-14.
Methods.
Transits of NGTS-14Ab were discovered in photometry from the Next Generation Transit Survey (NGTS). Follow-up transit photometry was conducted from several ground-based facilities, as well as extracted from TESS full-frame images. We combine radial velocities from the HARPS spectrograph with the photometry in a global analysis to determine the system parameters.
Results.
NGTS-14Ab has a radius that is about 30 per cent larger than that of Neptune (0.444 ± 0.030
R
Jup
) and is around 70 per cent more massive than Neptune (0.092 ± 0.012
M
Jup
). It transits the main-sequence K1 star, NGTS-14A, with a period of 3.54 days, just far away enough to have maintained at least some of its primordial atmosphere. We have also identified a possible long-period stellar mass companion to the system, NGTS-14B, and we investigate the binarity of exoplanet host stars inside and outside the Neptunian desert using
Gaia
.
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