BackgroundDespite numerous therapeutic options, safe and curative therapy is unavailable for most patients with chronic lymphocytic leukemia (CLL). A drawback of current therapies such as the ...anti-CD20 monoclonal antibody (mAb) rituximab is the elimination of all healthy B cells, resulting in impaired humoral immunity. We previously reported the identification of a patient-derived, CLL-binding mAb, JML-1, and identified sialic acid-binding immunoglobulin-like lectin-6 (Siglec-6) as the target of JML-1. Although little is known about Siglec-6, it appears to be an attractive target for cancer immunotherapy due to its absence on most healthy cells and tissues.MethodsWe used a target-specific approach to mine for additional patient-derived anti-Siglec-6 mAbs. To assess the therapeutic utility of targeting Siglec-6 in the context of CLL, T cell-recruiting bispecific antibodies (T-biAbs) that bind to Siglec-6 and CD3 were engineered into single-chain variable fragment–Fc and dual-affinity retargeting (DART)–Fc constructs. T-biAbs were evaluated for their activity in vitro, ex vivo, and in vivo.ResultsWe discovered the anti-Siglec-6 mAbs RC-1 and RC-2, which bind with higher affinity than JML-1 yet maintain similar specificity. Both JML-1 and RC-1 T-biAbs were effective at activating T cells and killing Siglec-6+ target cells. The RC-1 clone in the DART–Fc format was the most potent T-biAb tested and was the only anti-Siglec-6 T-biAb that eliminated Siglec-6+ primary CLL cells via autologous T cells at pathological T-to-CLL cell ratios. Tested at healthy T-to-B cell ratios, it also eliminated a Siglec-6+ fraction of primary B cells from healthy donors. The subpicomolar potency of the DART–Fc format was attributed to the reduction in the length and flexibility of the cytolytic synapse. Furthermore, the RC-1 T-biAb was effective at clearing MEC1 CLL cells in vivo and demonstrated a circulatory half-life of over 7 days.ConclusionSiglec-6-targeting T-biAbs are highly potent and specific for eliminating Siglec-6+ leukemic and healthy B cells while sparing Siglec-6− healthy B cells, suggesting a unique treatment strategy for CLL with diminished suppression of humoral immunity. Our data corroborate reports that T-biAb efficacy is dependent on synapse geometry and reveal that synapse architecture can be tuned via antibody engineering. Our fully human anti-Siglec-6 antibodies and T-biAbs have potential for cancer immunotherapy.Trial registration numberNCT00923507.
Abstract only Introduction: Level of activity has a reported association with sudden death, but cardiac causes are presumed by convention. We investigated association between activity level and ...causes of presumed SCD (pSCD) in the San Francisco POstmortem Systematic InvesTigation of Sudden Cardiac Death (POST SCD) Study. Methods: POST SCD is a prospective cohort study using autopsy, clinical records, and toxicology to adjudicate arrhythmic (potentially rescuable with implantable defibrillator) or non-arrhythmic (e.g., tamponade, overdose) causes among pSCDs (WHO defined) 18-90 years in San Francisco. We included all incident cases from 2/1/11-3/1/14 (n=525) and incident cases approximately every 3rd day from 3/1/14-12/31/21 (n=358). Activity level at time of pSCD was determined by forensic investigator reports. For unwitnessed deaths, activity level was inferred based on time of arrest and location found. Activity level was classified as: sleep, recently awoke (<10 min before death), awake with no activity (e.g., sitting), mild/moderate (e.g., bathing, feeding, walking), and rigorous (e.g., strenuous activity, sexual activity). Results: Of the total 883 pSCDs (mean 60 years, 73% male), 247 (28%) were sleeping, and 516 (58%) were awake at time of event. Cases with unclear circumstances (n=120, 14%) were excluded from analysis. Sleep was associated with non-cardiac cause of death (p=.01), specifically SUDEP (p=.02) and occult overdose (p<.001). Wakefulness was associated with SAD (p=0.005), pulmonary embolism (p=.007), and vascular damage (p=.004) (Table). Nearly all cases engaging in rigorous activity at time of death (n=32) were SADs (31/32, 97%) and male (29/32, 91%). Conclusions: Most sudden deaths in this 11-year countywide postmortem study occurred during wakefulness. Sleep was associated with non-arrhythmic cause (specifically SUDEP and occult overdose), while wakefulness and rigorous activity were associated with arrhythmic cause of sudden death.
Abstract only
Background:
Titin, encoded by
TTN
, is a sarcomeric protein necessary for normal cardiac and skeletal muscle function. Truncating variants in the A-band are a frequent cause of isolated ...and familial dilated cardiomyopathy (DCM) in living cohorts. Whether variants outside of the A-band confer arrhythmic risk remains unclear. We investigated the yield and distribution of
TTN
variants in a postmortem study of presumed sudden cardiac deaths (pSCDs) in San Francisco County.
Methods:
From 2/1/2011 to 12/31/2017, the Postmortem Systematic Investigation of Sudden Cardiac Death study performed complete autopsies on 889 incident deaths (age 16-90) meeting World Health Organization criteria for SCD (pSCD). Using clinical records, autopsy findings, and family history, we performed deep phenotyping to adjudicate underlying arrhythmic “SAD” (potentially rescuable with defibrillation) or non-arrhythmic “non-SAD” (tamponade, overdose, etc.) cause of pSCD. We performed clinical whole exome testing on cases with next of kin consent.
Results:
Of the 322 pSCDs tested (196 SAD, 126 non-SAD), we detected 5 truncating/splice variants located in non-A-band regions (p=0.03 vs. none found in the A-band) in 4 cases, all SAD. No truncating/splice variants were detected in 47 cases with autopsy evidence of DCM (cardiomegaly and short axis > 3.5cm). Overall, 89 cases had at least 1
TTN
variant of uncertain significance (VUS): 61 (68.5%) SADs and 28 (31.5%) non-SADs, with a trend towards more
TTN
VUSs among SADs (p =0.10). A total of 110 VUSs were found: 10 (9.1%) in the Z-disc, 38 (34.5%) in the I-band, 50 (45.5%) in the A-band, and 12 (10.9%) in the M-band.
TTN
VUSs clustered similarly throughout the gene in SADs and non-SADs.
Conclusion:
In this 7-year postmortem genetic study of unselected countywide sudden deaths using autopsy to adjudicate arrhythmic cause, we found
TTN
truncating/splice variants in non-A-band regions were associated with SAD and a trend toward association with SAD among
TTN
VUS carriers. In contrast to living cohorts with diagnosed DCM, no cases meeting autopsy criteria for DCM had a truncating/splice variant. Since non-survivors (i.e., SCDs) are underrepresented in DCM cohorts, our results suggest a potential role for non-A band
TTN
variants in arrhythmic risk.
Abstract only Introduction: Heart failure (HF) and left ventricular ejection fraction (EF) assessment have been hallmarks of sudden cardiac death (SCD) risk stratification for over 20 years. However, ...their sensitivity, specificity, and positive predictive value (PPV) for true arrhythmic death in the general population are unknown because nearly all SCD studies presume arhythmic causes. Aims: To define sensitivity, specificity, and PPV of current SCD risk stratification criteria for the autopsy-confirmed arrhythmic cause among countywide sudden deaths. Methods: POST SCD (POstmortem SysTematic Investigation of Sudden Cardiac Death) is a prospective cohort study using autopsy, clinical records, and toxicology to adjudicate arrhythmic (SAD; potentially rescuable with implantable defibrillator) or non-arrhythmic (non-SAD; e.g., tamponade, overdose) causes among presumed SCDs (pSCDs) in San Francisco County. We analyzed sensitivity, specificity, and PPV for syncope, EF≤35%, diagnosed HF, or the presence of any of 3 factors to discriminate SADs among pSCDs. Results: Between February 2011 and September 2022, 845 of 904 (93%) pSCDs 18-90 years had complete medical records available, of which 491 (58%) were SADs. Seventy-three pSCDs had history of syncope, with similar prevalence in SADs and non-SADs (p=0.4), while prevalence of HF was higher in SADs vs. non-SADs (88/49118% vs. 39/354 11%, p=0.003). EF assessment was performed in 206 pSCDs (24%, 133 SADs, 73 non-SADs); prevalence of EF ≤ 35% was similar between SADs and non-SADs (p=0.112). A greater proportion of SADs had ≥1 factor than non-SADs (122/49125% vs. 65/354 18%, p=0.015). Sensitivity of syncope, EF≤35%, HF, ≥1 factor for SAD was 9, 26, 17, 25%, specificity was 92, 82, 90, 82%, and PPV was 60, 73, 69, 65%, respectively. Conversely, 369 of 491 (75%) SADs had no risk factors before sudden death. Defibrillators were implanted in 4/491 (0.8%) SADs. Conclusions: In this 11-year countywide postmortem study, conventional risk factors had low sensitivity and PPV but high specificity for autopsy-confirmed arrhythmic cause of sudden death. Three-fourths of SADs had no risk factors before sudden death, highlighting the need for improved risk prediction in the general population.
Abstract only
Background:
Annual incidence of sudden cardiac death (SCD) is reported at 1% in cohorts with known hypertrophic cardiomyopathy (HCM), but these estimates presume arrhythmic cause and ...miss occult cases dying before diagnosis.
Hypothesis:
Prospective surveillance and postmortem investigation of community sudden deaths will uncover the true burden of presumed SCD (pSCD) and arrhythmic death (SAD) attributable to HCM.
Objectives:
Determine characteristics and precise contribution of HCM to population pSCD and SAD.
Methods:
POST SCD (POstmortem SysTematic Investigation of Sudden Cardiac Death) is a prospective cohort study using autopsy, clinical records, and toxicology to adjudicate arrhythmic (potentially rescuable with implantable defibrillator) or non-arrhythmic (e.g., tamponade, overdose) causes among pSCDs 0-90 years in San Francisco County. We included all incident cases from 2/1/11-3/1/14 (n=525) and approximately every 3rd day from 3/1/14-9/1/22 (n=497). We identified HCM victims via 3 parallel approaches: 1) pathology criteria; 2) echocardiogram (TTE) review; 3) genetic analysis.
Results:
Of 1022 pSCDs in the 11-year study period, we identified 13 cases with HCM, yielding a 2% contribution to arrhythmic death burden: 10 met pathology criteria; 2 via review of 203 TTEs (missed on initial report); 1 with pathogenic
ALPK3
mutation. Only 2 of 13 (15%) pSCDs with HCM had premortem diagnosis. A greater proportion of pSCDs with HCM had autopsy-confirmed arrhythmic cause than pSCDs without HCM (11/13 85% vs. 547/1009 54%, p=0.03). HCM contribution to pSCD burden decreased with age (p=0.003), highest among victims <35 years, accounting for 7.1% (6/84) of pSCDs and 9.4% (3/32) of SADs. Genetic testing of 317 consented pSCDs (5/12 meeting pathologic or TTE HCM criteria) yielded pathogenic mutations in 40% (2/5), and identified 1 additional case without clinical phenotype.
Conclusions:
In this 11-year countywide postmortem study, HCM meeting pathologic, clinical, or genetic criteria was associated with autopsy-confirmed arrhythmic cause of sudden death, accounting for 2% of SADs, highest in cases <35 years. As 85% of cases were undiagnosed before pSCD, the true burden of HCM-related sudden death may be substantially underestimated.
Bruton tyrosine kinase inhibitors (BTKis) are a preferred treatment of patients with chronic lymphocytic leukemia (CLL). Indefinite therapy with BTKis, although effective, presents clinical ...challenges. Combination therapy can deepen responses, shorten treatment duration, and possibly prevent or overcome drug resistance. We previously reported on a CD19/CD3-bispecific antibody (bsAb) that recruits autologous T-cell cytotoxicity against CLL cells in vitro. Compared with observations with samples from treatment-naïve patients, T cells from patients being treated with ibrutinib expanded more rapidly and exerted superior cytotoxic activity in response to the bsAb. In addition to BTK, ibrutinib also inhibits interleukin-2 inducible T-cell kinase (ITK). In contrast, acalabrutinib, does not inhibit ITK. Whether ITK inhibition contributes to the observed immune effects is unknown. To better understand how BTKis modulate T-cell function and cytotoxic activity, we cultured peripheral blood mononuclear cells (PBMCs) from BTKi-naive and ibrutinib- or acalabrutinib-treated CLL patients with CD19/CD3 bsAb in vitro. T-cell expansion, activation, differentiation, and cytotoxicity were increased in PBMCs from patients on treatment with either BTKi compared with that observed for BKTi-naïve patients. BTKi therapy transcriptionally downregulated immunosuppressive effectors expressed by CLL cells, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and CD200. CTLA-4 blockade with ipilimumab in vitro increased the cytotoxic activity of the bsAb in BTKi-naïve but not BTKi-treated PBMCS. Taken together, BTKis enhance bsAb-induced cytotoxicity by relieving T cells of immunosuppressive restraints imposed by CLL cells. The benefit of combining bsAb immunotherapy with BTKis needs to be confirmed in clinical trials.
•BTKis, independent of ITK inhibition, downregulate immunosuppressive effectors in CLL cells.•CD19/CD3-bispecific antibody-induced cytotoxicity is enhanced in PBMCs from patients treated with BTKis.
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•Epcoritamab-mediated killing of CLL cells by autologous T cells correlates with the effector-to-target ratio but not CD20 expression.•Epcoritamab efficacy is increased by concurrent use of a BTKi or ...venetoclax, supporting combination therapy.
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Chronic lymphocytic leukemia (CLL) is an immunosuppressive disease characterized by increased infectious morbidity and inferior antitumor activity of immunotherapies. Targeted therapy with Bruton's tyrosine kinase inhibitors (BTKis) or the Bcl-2 inhibitor venetoclax has profoundly improved treatment outcomes in CLL. To overcome or prevent drug resistance and extend the duration of response after a time-limited therapy, combination regimens are tested. Anti-CD20 antibodies that recruit cell- and complement-mediated effector functions are commonly used. Epcoritamab (GEN3013), an anti–CD3×CD20 bispecific antibody that recruits T-cell effector functions, has demonstrated potent clinical activity in patients with relapsed CD20+ B-cell non-Hodgkin lymphoma. Development of CLL therapy is ongoing. To characterize epcoritamab-mediated cytotoxicity against primary CLL cells, peripheral blood mononuclear cells from treatment-naive and BTKi-treated patients, including patients progressing on therapy, were cultured with epcoritamab alone or in combination with venetoclax. Ongoing treatment with BTKi and high effector-to-target ratios were associated with superior in vitro cytotoxicity. Cytotoxic activity was independent of CD20 expression on CLL cells and observed in samples from patients whose condition progressed while receiving BTKi. Epcoritamab induced significant T-cell expansion, activation, and differentiation into Th1 and effector memory cells in all patient samples. In patient-derived xenografts, epcoritamab reduced the blood and spleen disease burden compared with that in mice receiving a nontargeting control. In vitro, the combination of venetoclax with epcoritamab induced superior killing of CLL cells than either agent alone. These data support the investigation of epcoritamab in combination with BTKis or venetoclax to consolidate responses and target emergent drug-resistant subclones.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
8.
A heterotic Kodaira-Spencer theory at one-loop Ashmore, Anthony; Murgas Ibarra, Javier José; McNutt, David Duncan ...
The journal of high energy physics,
10/2023, Volume:
2023, Issue:
10
Journal Article
Peer reviewed
Open access
A
bstract
We consider a heterotic version of six-dimensional Kodaira-Spencer gravity derived from the heterotic superpotential. We compute the one-loop partition function and find it can be expressed ...as a product of holomorphic Ray-Singer torsions. We discuss its topological properties and potential gauge and gravitational anomalies. We show these anomalies can be cancelled using Green-Schwarz-like counter-terms. We also discuss the dependence on the background geometry, and in particular the choice of hermitian metric needed for quantisation. Given suitable topological constraints, this dependence may again be cancelled by the addition of purely background-dependent counter-terms. We also explain how our methods provide the one-loop partition functions of a large class of more general holomorphic field theories in terms of holomorphic Ray-Singer torsions.
A
bstract
We study the topological
G
2
and Spin(7) strings at 1-loop. We define new double complexes for supersymmetric NSNS backgrounds of string theory using generalised geometry. The 1-loop ...partition function then has a target-space interpretation as a particular alternating product of determinants of Laplacians, which we have dubbed the analytic torsion. In the case without flux where these backgrounds have special holonomy, we reproduce the worldsheet calculation of the
G
2
string and give a new prediction for the Spin(7) string. We also comment on connections with topological strings on Calabi-Yau and K3 backgrounds.
Objectives
To assess the literature on (i) the relevance of the presence of a minimum dimension of keratinized peri‐implant mucosa (KPIM) to maintain the health and stability of peri‐implant tissues, ...and; (ii) the surgical interventions and grafting materials used for augmenting the dimensions of the KPIM when there is a minimal amount or absence of it.
Material & Methods
Two systematic reviews complemented by expert opinion from workshop group participants served as the basis of the consensus statements, implications for clinical practice and future research, and were approved in plenary session by all workshop participants.
Results
Thirty‐four consensus statements, eight implications for clinical practice, and 13 implications for future research were discussed and agreed upon. There is no consistent data on the incidence of peri‐implant mucositis relative to the presence or absence of KPIM. However, reduced KPIM width is associated with increased biofilm accumulation, soft‐tissue inflammation, greater patient discomfort, mucosal recession, marginal bone loss and an increased prevalence of peri‐implantitis. Free gingival autogenous grafts were considered the standard of care surgical intervention to effectively increase the width of KPIM. However, substitutes of xenogeneic origin may be an alternative to autogenous tissues, since similar results when compared to connective tissue grafts were reported.
Conclusion
Presence of a minimum width of KPIM should be assessed routinely in patients with implant supported restorations, and when associated with pathological changes in the peri‐implant mucosa, its dimensions may be surgically increased using autogenous grafts or soft‐tissue substitutes with evidence of proven efficacy.
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BFBNIB, CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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