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The standard-of-care (SOC) for genomic testing of myeloid cancers primarily relies on karyotyping/fluorescent in situ hybridization (FISH) (cytogenetic analysis) and targeted gene panels (usually ≤54 genes) that harbor hotspot pathogenic variants (molecular genetic analysis). Despite this combinatorial approach, ~50% of myeloid cancer genomes remain cytogenetically normal, and the limited sequencing variant profiles obtained from targeted panels are unable to resolve the molecular etiology of many myeloid tumors. In this study, we evaluated the performance and clinical utility of combinatorial use of optical genome mapping (OGM) and a 523-gene next-generation sequencing (NGS) panel for comprehensive genomic profiling of 30 myeloid tumors and compared it to SOC cytogenetic methods (karyotyping and FISH) and a 54-gene NGS panel. OGM and the 523-gene NGS panel had an analytical concordance of 100% with karyotyping, FISH, and the 54-gene panel, respectively. Importantly, the IPSS-R cytogenetic risk group changed from very good/good to very poor in 22% of MDS (2/9) cases based on comprehensive profiling (karyotyping, FISH, and 54-gene panel vs. OGM and 523-gene panel), while additionally identifying six compound heterozygous events of potential clinical relevance in six cases (6/30, 20%). This cost-effective approach of using OGM and a 523-gene NGS panel for comprehensive genomic profiling of myeloid cancers demonstrated increased yield of actionable targets that can potentially result in improved clinical outcomes.

Certain cancer treatments, such as the poly (ADP-ribos) polymerase (PARP) inhibitors, have been shown to be effective in killing cancer cells exhibiting genome instability signatures indicative of homologous recombination deficiency (HRD). Hence, these signatures are used as biomarkers to inform treatment decisions and prognosis. There are three measurements of HRD signatures commonly employed: loss of heterozygosity (HRD-LOH), telomeric allelic imbalance (TAI) and large-scale state transition (LST). It has been shown that combining all three scores can better determine the HRD phenotype, leading to a higher clinical impact. Yet current HRD signature tests, used to estimate HRD, have low negative predictive value, and one possible reason is that current genomic technologies lack sensitivity to capture the full extent of somatic genomic rearrangements. Here, optical genome mapping (OGM) was used to detect large structural variants (SVs) and calculate a HRD score. OGM captures high molecular weight DNA to call SVs by aligning these molecules to the public reference genome. OGM can comprehensively detect insertions and deletions >5kbp, inversions, interchromosomal translocations, plus large interstitial copy number variation (CNV) and aneusomies. Subsequently, an automated script was developed to compute the HRD score, which is the summation of the three HRD signatures: HRD-LOH, the number of regions with a loss >15 Mbp but shorter than the whole chromosome; TAI, the number of regions of gain and loss >10Mbp that extend to a subtelomere but do not cross the centromere; and LST, the number of chromosomal breakpoints whose SV size >10Mb but not the whole chromosome. We applied this script on 20 samples of solid tumors and myeloid neoplasms, and the automated scores are concordant with expertly curated scores, confirming the validity of the calculation. We believe that OGM data combined with this automated analysis of HRD signatures is much more sensitive and accurate for detection of HRD signatures and that this will enable more precise prediction of drug response for multiple tumor types. Citation Format: Andy Wing Chun Pang, Kelsea Chang, Nikhil Sahajpal, Daniel Saul, Ravindra Kolhe, Alka Chaubey, Alex Hastie. Application of optical genome mapping to identify samples with homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6539.

The standard-of-care (SOC) for genomic testing of myeloid cancers primarily relies on karyotyping and fluorescent in situ hydridization (FISH) (cytogenetic analysis) and targeted gene panels (≤54 genes) that harbor hotspot pathogenic variants (molecular genetic analysis). Both cytogenetic and molecular testing workup is necessary for the identification and detection of large structural variants (SVs) and small variants like single nucleotide variants (SNV) and indels, respectively. Despite this combinatorial approach, ∼50% of myeloid cancer genomes remain cytogenetically normal, and the limited sequencing variant profiles obtained from targeted panels are unable to resolve the genetic etiology of these myeloid tumors. In this study, we evaluated the performance and clinical utility of optical genome mapping (OGM) and a 523-gene next-generation sequencing (NGS) panel for comprehensive genomic profiling of 15 myeloid tumors and compared it to SOC cytogenetic methods (karyotyping and FISH) and a 54-gene NGS panel. OGM and the 523-gene NGS panel were found to have an analytical concordance of 100% with karyotyping, FISH, and the 54-gene panel, respectively. Additionally, OGM better characterized and resolved the structural variants previously reported by karyotyping in five cases, such as identifying the genomic content of marker and ring chromosomes. OGM also identified several additional translocations and eleven copy number variations (CNVs), of which the CNVs were validated/confirmed by the 523-gene panel. The 523-gene panel identified seven additional clinically relevant SNVs (two tier 1A variants and five tier 2C variants, as per the ACMG/AMP guidelines) in four cases. The simultaneous visualization of SVs and small NGS detected sequence variants (SNVs and small indels) from OGM and 523-gene NGS panel, respectively in the NxClinical software v6.1 identified two clinically relevant compound heterozygous events in two samples. This study demonstrates the higher sensitivity, resolution, accuracy, and ability to reveal cryptic and clinically relevant novel variants in myeloid cancers as compared to SOC methodologies. Our cost-effective approach of using OGM and a 523-gene NGS panel for comprehensive genomic profiling of myeloid cancers will not only increase the yield of actionable targets leading to improved clinical outcomes but also help resolve our ongoing conundrum of apparently genomically normal myeloid cancers by providing more answers.

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Background Preliminary results of a new bariatric surgery program in a VA Medical Center using laparoscopic sleeve gastrectomy (LSG). Methods Prospective review of the first 50 patients who underwent LSG. Percentage change in body mass index (BMI), comorbidities, serum glucose, glycosylated hemoglobin (HbA1c), lipid profiles, and medications were recorded. Results Mean age was 52 years. Average BMI was 46 kg/m 2 . There were no mortalities or staple line leaks. The percentage excess BMI loss was 47% and 54% at 6 and 12 months, respectively. After 6 months, fasting glucose level decreased from 127 to 93 mg/dL, and mean glycosylated hemoglobin decreased from 6.8% to 5.7%. At 1-year follow-up evaluation, serum cholesterol decreased from 182 to 168 mg/dL, mean triglycerides from 179 to 93 mg/dL, low-density lipoprotein from 110 to 94 mg/dL, and high-density lipoprotein increased from 42 to 50 mg/dL. Conclusions Laparoscopic sleeve gastrectomy is safe and effective for morbidly obese VA patients and resulted in significant discontinuation of medication for hypertension, diabetes and hyperlipidemia.

Collaborative transmit beamforming is a form of communication where multiple transmitters cooperate to send a common message. If each transmitter properly controls the phase of its signal, the signals interfere constructively at the destination, translating in increased range, rate and energy e ciency. Collaborative beamforming has the potential to improve security and interference reduction by attenuating the signal transmitted in unintended directions. There are several challenges in collaborative transmit beamforming, like frequency synchronization, information sharing between nodes, and beampattern performance. This review focuses on the performance of collaborating nodes in terms of beampattern statistics when the transmitters are realized as a distributed ad hoc sensor network, and the nodes are randomly distributed over an area (Ochiai 2005, Mudumbai 2007). We review the design parameters necessary for the network to act as a distributed beamformer and support the nding of (Ochiai 2005) by simulations. The simulations treat the transmitting nodes as a virtual antenna array and collect relevant beampattern statistics.

Successful cleavage of animal cells requires co-ordinated regulation of the actomyosin contractile ring and cleavage furrow ingression. Data from a variety of systems implicate phosphoinositol lipids and calcium release as potential regulators of this fundamental process. Here we examine the requirement for various steps of the phosphatidylinositol (PtdIns) cycle in dividing crane fly (Nephrotoma suturalis) spermatocytes. PtdIns cycle inhibitors were added to living cells after cleavage furrows formed and began to ingress. Inhibitors known to block PtdIns recycling (lithium), PtdIns phosphorylation (wortmannin, LY294002) or phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] hydrolysis [U73122 (U7)] all stopped or slowed furrowing. The effect of these drugs on cytokinesis was quite rapid (within 0-4 minutes), so continuous metabolism of PtdIns appears to be required for continued cleavage furrow ingression. U7 caused cleavage furrow regression concomitant with depletion of F-actin from the contractile ring, whereas the other inhibitors caused neither regression nor depletion of F-actin. That U7 depletes furrow-associated actin seems counterintuitive, as inhibition of phospholipase C would be expected to increase cellular levels of PtdIns(4,5)P2 and hence increase actin polymerization. Our confocal images suggest, however, that F-actin might accumulate at the poles of U7-treated cells, consistent with the idea that PtdIns(4,5)P2 hydrolysis may be required for actin filaments formed at the poles to participate in contractile ring assembly at the furrow.

This dissertation presents a model of the human sentence interpretation process, which attempts to meet criteria of adequacy imposed by the different paradigms of sentence interpretation. These include the need to produce a high-level interpretation, to embed a linguistically motivated grammar, and to be compatible with psycholinguistic results on sentence processing. The model includes a theory of grammar called Construction-Based Interpretive Grammar (CIG) and an interpreter which uses the grammar to build an interpretation for single sentences. An implementation of the interpreter has been built called Sal. Sal is an on-line interpreter, reading words one at a time and updating a partial interpretation of the sentence after each constituent. This constituent-by-constituent interpretation is more fine-grained and hence more on-line than most previous models. Sal is strongly interactionist in using both bottom-up and top-down knowledge in an evidential manner to access a set of constructions to build interpretations. It uses a coherence-based selection mechanism to choose among these candidate interpretations, and allows temporary limited parallelism to handle local ambiguities. Sal's architecture is consistent with a large number of psycholinguistic results. The interpreter embodies a number of strong claims about sentence processing. One claim is uniformity, with respect to both representation and process. In the grammar, a single kind of knowledge structure, the grammatical construction, is used to represent lexical, syntactic, idiomatic, and semantic knowledge. CIG thus does not distinguish between the lexicon, the idiom dictionary, the syntactic rule base, and the semantic rule base. Uniformity in processing means that there is no distinction between the lexical analyzer, the parser, and the semantic interpreter. Because these kinds of knowledge are represented uniformly, they can be accessed, integrated, and disambiguated by a single mechanism. A second claim the interpreter embodies is that sentence processing is fundamentally knowledge-intensive and expectation-based. The representation and integration of constructions uses many diverse types of linguistic knowledge. Similarly, the access of constructions is sensitive to top-down and bottom-up, syntactic and semantic knowledge, and the selection of constructions is based on coherence with grammatical knowledge and the interpretation.

Lymphopenia is the hallmark of HIV infection and is thought to be mediated by virus infection and subsequent killing of CD4+ T cells. However, recent data suggests that decrease in peripheral CD4+ T cells may initially involve sequestration of these cells in secondary lymphoid tissues (SLT). T cell homing to SLT is facilitated by SLT-specific chemokines, CCL19 and CCL21 while egress from SLT requires expression of functional sphingosine-1-phosphate (S1P) receptors. As lymphadnopathy is observed in most HIV-1 infected individuals, we investigated the potential of HIV-1 envelope glycoprotein, gp120, to affect parameters of T cell homing to SLT. Normal human T cells were exposed to gp120 for 1 to 24h prior to migration induced by CCL19 or CCL21. We also investigated the effects of gp120 on responsiveness to S1P induced migration. We found that exposure to gp120 for 1h augmented, by 2-fold, chemoattraction induced by CCL19 and CCL21, but did not effect migration induced by the SLT independent chemokine CCL11. Conversely, these cells became completely unresponsive to S1P induced migration (2–3 fold migration blocked to 0). The gp120 mediated inhibition of migration was completely reversed by the p56lck inhibitor herbimycin A, indicating a requirement of CD4 signaling. Taken together our data indicates that gp120 alone could facilitate CD4+ T cell homing and sequestration in the SLT of HIV infected indiivduals.

Chandini (A Bride For The Moon) is an art/science project led by RD how they collaborated, in response to different opportunities and changing circumstances, the obstacles they encountered and how the public engaged with their artworks at events and festivals between 2017 and 2019 in the UK and India.