We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of ...undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration.
This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per μL or lymph nodes >5 cm in diameter, day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes <10
) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort.
Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 59% of 39), fatigue (21 54%), neutropenia (20 51%), and bruising (20 51%), and the most common adverse event at grade 3 or worse was neutropenia (seven 18%) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli.
BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics.
Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.
Purpose: Maturation of the ability to recognize target speech in the presence of a two-talker speech masker extends into early adolescence. This study evaluated whether children benefit from ...differences in fundamental frequency (fsubscript o) contour depth between the target and masker speech, a cue that has been shown to improve recognition in adults. Method: Speech stimuli were recorded from talkers using three speaking styles, with fsubscript o contour depths that were Flat, Normal, or Exaggerated. Targets were open-set, declarative sentences produced by a female talker, and maskers were two streams of concatenated sentences produced by a second female talker. Listeners were children (ages 5-17 years) and adults (ages 18-24 years) with normal hearing. Each listener was tested in one of the three masker styles paired with all three target styles. Speech recognition thresholds (SRTs) corresponding to 50% correct were estimated by fitting psychometric functions to adaptive track data. Results: For adults, performance did not differ significantly across conditions with matched speaking styles. A mismatch benefit was observed when combining Flat targets with the Exaggerated masker and Exaggerated targets with the Flat masker, and for both Flat and Exaggerated targets paired with the Normal masker. For children, there was a significant effect of age in all conditions. Flat targets in the Flat masker were associated with lower SRTs than the other two matched conditions, and a mismatch benefit was observed for young children only when the target fsubscript o contour was less variable than the masker fsubscript o contour. Conclusions: Whereas child-directed speech often has exaggerated pitch contours, young children were better able to recognize speech with less variable fsubscript o. Age effects were observed in the benefit of mismatched speaking styles for some conditions, which could be related to differences in baseline SRTs rather than differences in segregation abilities.
•Energy in speech above 8 kHz can impact children's speech-in-speech recognition.•Extended high frequencies improved children's open-set sentence recognition.•A small change in masker head ...orientation improved speech recognition performance.•Children benefitted to a similar degree as adults from extended high frequencies.•Better high frequency hearing did not result in more benefit for children than adults.
While the audible frequency range for humans spans approximately 20 Hz to 20 kHz, children display enhanced sensitivity relative to adults when detecting extended high frequencies (frequencies above 8 kHz; EHFs), as indicated by better pure tone thresholds. The impact that this increased hearing sensitivity to EHFs may have on children's speech recognition has not been established. One context in which EHF hearing may be particularly important for children is when recognizing speech in the presence of competing talkers. In the present study, we examined the extent to which school-age children (ages 5-17 years) with normal hearing were able to benefit from EHF cues when recognizing sentences in a two-talker speech masker. Two filtering conditions were tested: all stimuli were either full band or were low-pass filtered at 8 kHz to remove EHFs. Given that EHF energy emission in speech is highly dependent on head orientation of the talker (i.e., radiation becomes more directional with increasing frequency), two masker head angle conditions were tested: both co-located maskers were facing 45°, or both were facing 60° relative to the listener. The results demonstrated that regardless of age, children performed better when EHFs were present. In addition, a small change in masker head orientation also impacted performance, with better recognition at 60° compared to 45°. These findings suggest that EHF energy in the speech signal above 8 kHz is beneficial for children in complex listening situations. The magnitude of benefit from EHF cues and talker head orientation cues did not differ between children and adults. Therefore, while EHFs were beneficial for children as young as 5 years of age, children's generally better EHF hearing relative to adults did not provide any additional benefit.
Understanding humoral responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics, therapeutics, and vaccines. Deep serological profiling of 232 ...coronavirus disease 2019 (COVID-19) patients and 190 pre-COVID-19 era controls using VirScan revealed more than 800 epitopes in the SARS-CoV-2 proteome, including 10 epitopes likely recognized by neutralizing antibodies. Preexisting antibodies in controls recognized SARS-CoV-2 ORF1, whereas only COVID-19 patient antibodies primarily recognized spike protein and nucleoprotein. A machine learning model trained on VirScan data predicted SARS-CoV-2 exposure history with 99% sensitivity and 98% specificity; a rapid Luminex-based diagnostic was developed from the most discriminatory SARS-CoV-2 peptides. Individuals with more severe COVID-19 exhibited stronger and broader SARS-CoV-2 responses, weaker antibody responses to prior infections, and higher incidence of cytomegalovirus and herpes simplex virus 1, possibly influenced by demographic covariates. Among hospitalized patients, males produce stronger SARS-CoV-2 antibody responses than females.
Identifying functional brown adipose tissue (BAT) has provided new hope for obesity treatment and prevention. Functional BAT includes classical BAT and brown-like adipose tissue converted from white ...adipose tissue. By promoting thermogenesis (i.e., heat production)
uncoupling protein 1 (UCP1), functional BAT can increase energy expenditure and aid obesity treatment and prevention. Naringenin (NAR) is a flavanone primarily found in citrus fruits. NAR has been reported to decrease body weight, increase energy expenditure in treated mice, and promote browning in human adipocytes. Here, we examined the effects of NAR on 3T3-L1 adipocytes' browning and β-adrenergic agonist isoproterenol (ISO)-stimulated thermogenic activation and classical murine brown adipogenesis. In addition, we demonstrated the signaling pathways and involvement of peroxisome proliferator-activated receptor gamma (PPARγ) in the process. We found that NAR did not increase
mRNA expression at the basal (i.e., non-ISO stimulated) condition. Instead, it enhanced
and
α up-regulation and thermogenesis under ISO-stimulated conditions in 3T3-L1 adipocytes. NAR promoted protein kinase A (PKA) activation and phosphorylation of p38 MAPK downstream of ISO stimulation and activated PPARγ. Pharmacological inhibition of either PKA or p38 and PPARγ knockdown attenuated
up-regulation by NAR. Moreover, NAR promoted brown adipogenesis by increasing lipid accumulation, brown marker expression, and thermogenesis in murine brown adipocytes, which was also attenuated by PPARγ knockdown. Together, our results suggest that NAR may promote the development of functional BAT in part through PPARγ activation. NAR's role in combating human obesity warrants further investigation.
BACKGROUNDBrain metastases are a significant cause of mortality and morbidity for patients with melanoma. We hypothesize that the development of brain metastases may be explained by molecular ...heterogeneity between primary cutaneous melanoma (PCM) or extracranial (ECM) and brain (MBM) melanoma metastases. MATERIALS AND METHODSWe compared next-generation sequencing, tumor mutational burden (TMB), and immunohistochemical staining for PD-L1 expression, among 132 MBM, 745 PCM, and 1190 ECM. RESULTSThe most common genetic alterations among MBM included: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Four genes were found with higher frequency among MBM compared to PCM or ECM: BRAF (52.4% v 40.4% v 40.9%), SETD2 (11.9% v 1.9% v 3.9%), PBRM1 (7.5% v 1.6% v 2.6%), and DICER1 (4.4% v 0.6% v 0.4%). MBM showed higher TMB (p = .04) and higher PD-L1 expression (p = .002), compared to PCM. PD-L1 expression was slightly higher among MBM compared to ECM (p = .042), but there was no difference between TMB (p = .21). CONCLUSIONSOur findings suggest a unique molecular profile for MBM, including higher rates of BRAF mutations, higher TMB and higher PD-L1 expression, and also implicate chromatin remodeling in the pathogenesis of MBM.
Background:
The Ohio State University Wexner Medical Center identified a cluster of coronavirus disease 2019 (COVID-19) cases on an inpatient geriatric stroke care unit involving both patients and ...staff. The period of suspected severe acute respiratory coronavirus virus 2 (SARS-CoV-2) transmission and exposure on the unit was December 20, 2020, to January 1, 2021, with some patients and staff developing symptoms and testing positive within the 14 days thereafter.
Methods:
An epidemiologic investigation was conducted via chart review, staff interviews, and contact tracing to identify potential patient and staff linkages. All staff who worked on the unit were offered testing regardless of the presence of symptoms as well as all patients admitted during the outbreak period.
Results:
In total, 6 patients likely acquired COVID-19 in the hospital (HCA). An additional 6 patients admitted to the unit during the outbreak period subsequently tested positive but had other possible exposures outside the hospital (Fig. 1). One patient failed to undergo COVID-19 testing on admission but tested positive early in the cluster and is suspected to have contributed to patient to employee transmission. Moreover, 32 employees who worked on the unit in some capacity during this period tested positive, many of whom became symptomatic during their shifts. In addition, 18 employees elected for asymptomatic testing with 3 testing positive; these were included in the total. Some staff also identified potential community exposures. Additionally, staff reported an employee who was working while symptomatic with inconsistent mask use (index employee) early in the outbreak period. The index employee likely contributed to employee transmission but had no direct patient contact. Our epidemiologic investigation ultimately identified 12 employees felt to be linked to transmission based on significant, direct patient care provided to the patients within the outbreak period (Fig. 1). In addition, 3 employees had an exposure outside the hospital indicating likely community transmission.
Conclusions:
Transmission was felt to be multidirectional and included employee-to-employee, employee-to-patient, and patient-to-employee transmission in the setting of widespread community transmission. Interventions to stop transmission included widespread staff testing, staff auditing regarding temperature and symptom monitoring, and re-education on infection prevention practices. Particular focus was placed on appropriate PPE use including masking and eye protection, hand hygiene, and cleaning and disinfection practices throughout the unit. SARS-CoV-2 admission testing and limited visitation remain important strategies to minimize transmission in the hospital.
Funding:
No
Disclosures:
None
A series of cationic amphiphiles, each with an aromatic core, was prepared and investigated for antimicrobial properties. The synthesized amphiphiles in this study are bicephalic (double-headed) in ...that they each possess two trimethylammonium head groups and a single linear alkoxy tail. Minimum inhibitory and minimum bactericidal concentrations of these amphiphiles were in the low micromolar range. Antimicrobial activities are highly sensitive to the chain length of the hydrophobic region, and modestly reliant on the relative positioning of the head groups on the aromatic core. These trends were more pronounced in time kill assays, wherein longer chain compounds required significantly shorter times to completely kill bacteria. Microscopy suggested that the mode of cell death was lysis. Strong inhibition was observed with both biscationic compounds and monocationic comparisons against Gram-positive bacteria; only biscationic amphiphiles maintained good activity versus the Gram-negative bacteria tested. These observations provide direction for future antimicrobial structural investigations.
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► A series of biscationic bicephalic (double-headed) amphiphiles was prepared. ► Amphiphiles were evaluated for antimicrobial activity. ► Inhibition was observed for both Gram-positive and Gram-negative bacteria. ► Activity was highly sensitive to hydrophobic chain length. ► Activity was modestly reliant on polar head-group architecture.
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