10-fold Reduction Research Articles

Abstract 1743: miR-1307-5p reverses cisplatin resistance in oral squamous cell carcinomas (OSCC) by targeting EHF, a modulator of stemness genes

Abstract Background: We have previously identified miR-1307-5p is exclusively expressed in OSCC tumors and is significantly upregulated in chemo-resistant patients. In this study, we investigate the mechanism of miR-1307-5p in conferring therapeutic refractoriness and demonstrate reversal of cisplatin induced chemoresistance. This study provides a potentially new therapeutic target for treating recurrent oral carcinomas. Methods: Expression of miR-1307-5p was validated in OSCC patients (n=86), OECM1 cell line and cisplatin resistant CD44+ subpopulation. miR-1307-5p was knocked down in OECM1 and CD44+ cells and its effect on cell proliferation, apoptosis, cell cycle, migration, invasion and sphere forming abilities was measured. We examined the transcriptome of these patients (n=30) and combined this data with The Cancer Genome Atlas (TCGA) dataset for target prediction (TargetScan) and network analysis (Ingenuity Pathway Analysis). The hub genes were considered to be potential targets of miR-1307-5p and were validated by luciferase assay and Western Blotting. Results: Sequencing analysis revealed exclusive expression of miR-1307-5p in the OSCC patient cohort with significant upregulation in chemo-resistant cases (FC:4.82 ± 2.38, p-value:0.01). miR-1307-5p upregulation separated the chemoresistant and remission cohorts (p<0.05). Transfection-mediated silencing of miR-1307-5p in OECM1(FC:0.009 ± 1.5, p:0.01) and CD44+ (FC:0.06 ± 2.3, p:0.01) cells restrained the cell proliferation rates (p<0.01) and revealed a significant sub G0 population of OECM1 (20±5%) and CD44+(18.7±3%) cells, indicating early apoptosis. A significant Annexin V+/PI- population (OECM1: 40%±3.36%; CD44+: 23%±3.36%) confirmed induction of apoptosis, post-silencing. A 2 fold reduction in the sphere-forming ability and invasive potentials of CD44+ cells observed post-knockdown (p>0.05). Combinatorial treatment of cisplatin and miR-1307-5p inhibitor reduced the proliferation rate of CD44+ cells by 66.23% in comparison to standalone treatment of the inhibitor (p:0.034). Thus, indicating role of miR-1307-5p in reversal of chemo-resistance. Gene target identification revealed miR-1307-5p could promote therapeutic refractoriness by suppressing the expression of EHF, which regulates cancer stem cell renewal by targeting Sox-2, Oct-4 and Nanog. Dual-luciferase gene reporter assay revealed direct suppression of EHF by miR-1307-5p. Further, knockdown of miR-1307-5p increased endogenous EHF mRNA and protein expression in cancer cells. Conclusion: miR1307-5p downregulates EHF which is an inhibitor of many stemness genes like Sox-2, Oct-4 and Nanog. Knockdown of miR-1307-5p reverses Cisplatin resistance by upregulating EHF thus suppressing the emergence of cancer stem cells in OSCC. Citation Format: Aditi Patel, Shanaya Patel, Shreya Lotia, Vivek Tanavde. miR-1307-5p reverses cisplatin resistance in oral squamous cell carcinomas (OSCC) by targeting EHF, a modulator of stemness genes [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 1743.

Synergy Potential of Ursolic Acid-Based Hybrid Molecules

Background: Ursolic acid (UA, 3β-hydroxy-urs-12-en-28-oic acid), a pentacyclic triterpenoid from various medicinal plants, has been blessed with proven biological effects, including anti-inflammatory, anticancer, antidiabetic, antioxidant and antibacterial, but its bioavailability and solubility limit its clinical application. Objective: Synthesis of UA-based hybrid molecules to explore their antibacterial and synergy potential in combination with azithromycin (AZT) for the treatment of multidrug-resistant (MDR) bacterial infections. Methods: Hybrid molecules of UA with menthol, eugenol, and nalidixic acid (NAL) along with some other ester derivatives were synthesized, and evaluated for their antibacterial and synergy potential in combination with AZT against the clinical isolate of Escherichia coli in terms of their minimum inhibitory concentration (MIC), fold reduction in MIC, fractional inhibitory concentration index (FICI) and type of interaction. In silico screening of pharmacokinetic parameters, docking affinity against efflux pump proteins AcrA, AcrB, and TolC was performed on the most potent derivative 7 (3-O-nalidixoyl UA). Results: Derivative 7 showed MIC of 62.5 µg/mL and a strong synergistic effect with AZT reducing the MIC of AZT from 100 to 0.19 µg/mL (512-fold reduction) against E. coli at a concentration of 12.5 µg/mL. Other derivatives neither showed antibacterial activity of their own (MIC > 1000 µg/mL) nor any significant synergistic interaction in combination with AZT. The in silico studies on 7 revealed improved druggability parameters over the parent UA and NAL. Conclusion: The findings highlight derivative 7 as strong synergistic agent in combination with AZT which may be further investigated to render its efficient use for the treatment of MDR bacterial infections.

Experimental Assessment of PCA and DT Classification for Streamlined Position Reconstruction in Anger Cameras

In this article, we present a study of machine learning (ML) algorithms to simplify the computation of the planar scintillation coordinates in Anger Cameras for emission tomography applications. Two ML-based techniques for data inference and one technique to speed-up the training procedure are explored within the framework of a multimodal SPECT scanner. First, the use of principal component analysis (PCA), a dimensionality reduction algorithm, is explored to reduce the computational complexity of the maximum-likelihood statistical estimation method. The analysis indicates a <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\sim 3$ </tex-math></inline-formula> -fold reduction of computational complexity for typical Anger Camera architectures (with 72 channels). Second, the estimation of the scintillation coordinates is formulated as a classification problem, addressed by means of a decision tree (DT) classifier. No degradation of the achievable intrinsic spatial resolution <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$(\sim 1.2$ </tex-math></inline-formula> -mm FWHM) of the detection module was observed when applying PCA (reducing from 72 to 25 components). The DT classifier was trained on experimental data obtained using a parallel-hole collimator: again no degradation of spatial resolution is observed and the computation cost is reduced by more than two orders of magnitude. Finally, in order to overcome the limits of a cumbersome training procedure involving the translation of the collimator, data augmentation was successfully leveraged for the generation of artificial data.

Editor's Choice – Estimated Radiation Dose to the Operator During Endovascular Aneurysm Repair

To estimate operator organ doses from fluoroscopically guided infrarenal endovascular aneurysm repair (EVAR) procedures, using the detailed exposure information contained in radiation dose structured reports. Conversion factors relating kerma area product (PKA) to primary operator organ doses were calculated using Monte Carlo methods for 91 beam angles and seven x-ray spectra typical of clinical practice. A computer program was written, which selects the appropriate conversion factor for each exposure listed in a structured report and multiplies it by the respective PKA. This system was used to estimate operator doses for 81 EVAR procedures for which structured reports were available. The impact of different shielding scenarios and variations in operator position was also investigated. Without any shielding, the median estimated effective dose was 113 μSv (interquartile range [IQR] 71, 252 μSv). The highest median organ doses were for the colon (154 μSv, IQR 81, 343) and stomach (133 μSv, IQR 76, 307). These dose estimates represent all exposures, including fluoroscopy and non-fluoroscopic digital acquisitions. With minimal shielding provided by 0.25 mm of Pb covering the torso and upper legs, the effective dose was reduced by a factor of around 6. With additional shielding from ceiling and table shields, a 25 to 50 fold reduction in dose is achievable. Estimated doses were highest where the primary beam was pointed directly away from the operator. The models suggest that with optimal use of shielding, operator doses can be reduced to levels equivalent to one to two days of natural background exposure and well below statutory dose limits.

Protection from COVID-19 disease in hamsters vaccinated with subunit SARS-CoV-2 S1 mucosal vaccines adjuvanted with different adjuvants.

Adjuvant plays an important role in directing the immune responses induced by vaccines. In previous studies, we have shown that a mucosal SARS-CoV-2 S1 subunit vaccine adjuvanted with a combination of CpG, Poly I:C and IL-15 (named CP15) induced effective mucosal and systemic immunity and conferred nearly sterile protection against SARS-CoV-2 viral replication in macaque models. In this study, we used a hamster model, which mimics the human scenario and reliably exhibits severe SARS-CoV-2 disease similar to hospitalized patients, to investigate the protection efficacy of the vaccines against COVID-19 disease. We compared the weight loss, viral loads (VLs), and clinical observation scores of three different vaccine regimens. All three regimens consisted of priming/boosting with S1 subunit vaccines, but adjuvanted with alum and/or CP15 administrated by either intramuscular (IM) or intranasal (IN) routes: Group 1 was adjuvanted with alum/alum administrated IM/IM; Group 2 was alum-IM/CP15-IN; and Group 3 was CP15-IM/CP15-IN. After challenge with SARS-CoV-2 WA strain, we found that the alum/CP15 group showed best protection against weight loss, while the CP15 group demonstrated best reduction of oral SARS-CoV-2 VLs, suggesting that the protection profiles were different. Sex differences for VL and clinical scores were observed. Humoral immunity was induced but not correlated with protection. Moreover, S1-specific binding antibody titers against beta, omicron BA.1, and BA.2 variants showed 2.6-, 4.9- and 2.8- fold reduction, respectively, compared to the Wuhan strain. Overall, the data suggested that adjuvants in subunit vaccines determine the protection profiles after SARS-CoV-2 infection and that nasal/oral mucosal immunization can protect against systemic COVID-19 disease.

Topological charge pumping with subwavelength Raman lattices

Recent experiments demonstrated deeply subwavelength lattices using atoms with $N$ internal states Raman coupled with lasers of wavelength $\ensuremath{\lambda}$. The resulting unit cell was $\ensuremath{\lambda}/2N$ in extent, an $N$-fold reduction compared to the usual $\ensuremath{\lambda}/2$ periodicity of an optical lattice. For resonant Raman coupling, this lattice consists of $N$ independent sinusoidal potentials (with period $\ensuremath{\lambda}/2$) displaced by $\ensuremath{\lambda}/2N$ from each other. We show that detuning from Raman resonance induces tunneling between these potentials. Temporally modulating the detuning couples the $s$ and $p$ bands of the potentials, creating a pair of coupled subwavelength Rice-Mele chains. This operates as a topological charge pump that counterintuitively can give half the displacement per pump cycle of each individual Rice-Mele chain separately. We analytically describe this behavior in terms of infinite-system Chern numbers and numerically identify the associated finite-system edge states.

Sigma Delta Quantization for Images

AbstractIn signal quantization, it is well‐known that introducing adaptivity to quantization schemes can improve their stability and accuracy in quantizing bandlimited signals. However, adaptive quantization has only been designed for one‐dimensional signals. The contribution of this paper is two‐fold: (i) we propose the first family of two‐dimensional adaptive quantization schemes that maintain the same mathematical and practical merits as their one‐dimensional counterparts, and (ii) we show that both the traditional 1‐dimensional and the new 2‐dimensional quantization schemes can effectively quantize signals with jump discontinuities, which immediately enable the usage of adaptive quantization on images. Under mild conditions, we show that by using adaptivity, the proposed method is able to reduce the quantization error of images from the presently best to the much smaller , where s is the number of jump discontinuities in the image and P () is the total number of samples. This ‐fold error reduction is achieved via applying a total variation norm regularized decoder, whose formulation is inspired by the mathematical super‐resolution theory in the field of compressed sensing. Compared to the super‐resolution setting, our error reduction is achieved without requiring adjacent spikes/discontinuities to be well‐separated, which ensures its broad scope of application.We numerically demonstrate the efficacy of the new scheme on medical and natural images. We observe that for images with small pixel intensity values, the new method can significantly increase image quality over the state‐of‐the‐art method. © 2022 Wiley Periodicals, Inc.

Ultrafast Ultrasound Localization Microscopy by Conditional Generative Adversarial Network.

Ultrasound localization microscopy (ULM) overcomes the acoustic diffraction limit and enables the visualization of microvasculature at subwavelength resolution. However, challenges remain in ultrafast ULM implementation, where short data acquisition time, efficient data processing speed, and high imaging resolution need to be considered simultaneously. Recently, deep learning (DL)-based methods have exhibited potential in speeding up ULM imaging. Nevertheless, a certain number of ultrasound (US) data ( L frames) are still required to accumulate enough localized microbubble (MB) events, leading to an acquisition time within a time span of tens of seconds. To further speed up ULM imaging, in this article, we present a new DL-based method, termed as ULM-GAN. By using a modified conditional generative adversarial network (cGAN) framework, ULM-GAN is able to reconstruct a superresolution image directly from a temporal mean low-resolution (LR) image generated by averaging l -frame raw US images with l being significantly smaller than L . To evaluate the performance of ULM-GAN, a series of numerical simulations and phantom experiments are both implemented. The results of the numerical simulations demonstrate that when performing ULM imaging, ULM-GAN allows ∼40 -fold reduction in data acquisition time and ∼61 -fold reduction in computational time compared with the conventional Gaussian fitting method, without compromising spatial resolution according to the resolution scaled error (RSE). For the phantom experiments, ULM-GAN offers an implementation of ULM with ultrafast data acquisition time ( ∼0.33 s) and ultrafast data processing speed ( ∼0.60 s) that makes it promising to observe rapid biological activities in vivo.

Folic acid-poly(N-isopropylacrylamide-maltodextrin) nanohydrogels as novel thermo-/pH-responsive polymer for resveratrol breast cancer targeted therapy

BackgroundThe long-term sequelae and serious side effects of conventional breast cancer chemotherapy due to ubiquitous biodistribution and systemic toxicity remain the main obstacle to success in clinic. Recent anticancer research rely on tailoring smart carriers to overcome these drawbacks. In this regard, numerous stimuli-responsive polymers have been assembled and successfully employed as smart carriers various chemotherpeutic agents due to their intrinsic tumor targeting properties. Among which, poly(N-isopropylacrylamide (PNIPAM) has gained increasing attention being amenable to various chemical modifications for tuning its intrinsic thermoresponsivity or endowing additional stimulus responsiveness. This work aims to develop PNIPAM-maltodextrin nanohydrogels (PNIPAM-MD NGs) decorated with folic acid (FA) as smart breast cancer-targeted stimuli-responsive delivery system to the natural polyphenol resveratrol (RSV) suffering from low bioavailaibity. ResultsPNIPAM-MD was synthesized by graft copolymerization, characterized and evaluated for its modulated stimuli-responsivity. The PNIPAM-based copolymer was coupled with FA, the breast cancer active targeting ligand. The FA-PNIPAM-MD NGs core was loaded RSV, then subjected to in vitro and in vivo evaluation. Results showed that the developed RSV-loaded FA-PNIPAM-MD (F3) NGs displayed dual thermo- and pH-responsivities, high drug-loading capacity (8.31 wt%,) and excellent physical and serum stability. The targeted formula F3 exhibited enhanced in vitro anti-breast cancer potency as evident by 7.4 folds reduction in the IC50 of free RSV and significant MCF-7 cellular uptake. In breast cancer-bearing mice, F3 suppressed the tumor growth, lowered VEGF-1 and Ki-67 expression levels, and induced apoptosis via upregulating caspase-3. ConclusionOverall, the PNIPAM-MD NGs as well as its FA-decorated breast cancer-targted NGs could serve as promising smart nanocarrier for efficient RSV brest cancer delivery. It could be safely deduced that the assembled FA-PNIPAM-MD F3 NGs enabled sequestering the therapeutic cargo (RSV) in normal tissue and released it in tumor site, thus guarding against its rapid metabolism and maximizing its accumulation in the cancer tissue as evidenced by the remarkable tumor growth suppression noticed in the targeted RSV/FA-PNIPAM-MD F3 NGs-treated mice compared to that in the free RSV-treated group. Hence, The fabricated nanohydrogels may be further employed for smart delivery of various anti-breast cancer agents.

Reducing the Incidence of PONV in Facial Feminization Surgery through a Standardized Anesthetic Regimen

Introduction: Postoperative nausea and vomiting (PONV) continues to be a major issue for patients undergoing facial feminization surgery (FFS In this study, we aim to examine risk factors and the incidence of PONV before and after the implementation of a new anesthetic and antiemetic regimen throughout all surgical stages; preoperative, intraoperative, and postoperative. Methods: A retrospective cohort study was performed on 158 patients who received FFS at an academic medical institution’s center for transgender medicine and surgery between 2018 and 2022. Of these, 117 patients underwent FFS with no specific antiemetic regimen, and were given antiemetics for nausea or vomiting as seen fit by their surgeon, and 41 patients underwent FFS with the new intervention. Odds Ratios were computed via logistic regression using RStudio to adjust for age, BMI, and smoking status (defined as a patient reported “ever smoker” vs “never smoker”). Results: 80 out of 117 (68%) patients on the old regimen experienced PONV, compared with 8 out of 41 (19%) of patients on the new regimen. After adjusting for age, BMI, and smoking status, the new regimen is associated with a 6 fold reduction in PONV, with a calculated odds ratio of 0.15 (95% CI: 0.06, 0.36; p = 3.9x10^-5) compared with the old regimen. Conclusion: Among patients undergoing FFS, a novel antiemetic regimen reduced the incidence of PONV by 6-fold when compared with standard of care. By introducing an appropriate antiemetic prophylaxis, tailored specifically to curb PONV, providers can ensure a more comfortable postoperative experience for patients.

CLL-515 Antibody Responses Against SARS-CoV-2 Variants after Booster Vaccination in Patients With B Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia

Context: Patients with B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL) are at increased risk of morbidity and mortality from SARS-CoV-2 infection. Anti-SARS-CoV-2 vaccination is highly recommended for these patients but their antibody responses after the initial vaccination series is impaired, particularly when measured against SARS-CoV-2 variants. Objective: To assess antibody responses against SARS-CoV-2 variants after booster vaccination in NHL/CLL patients. Design: We designed a single center, prospective, observational study and collected blood and clinical data on 69 patients who received an approved booster dose. Antibody binding against SARS-CoV-2 spike of the original strain and of variants of concern were measured using a multiplex assay. Live-virus neutralization against Delta, Omicron, and the ancestral WA1/2020 strains were measured by focus reduction neutralization test (FRNT). Correlation between vaccine response and clinical factors were determined. Results: Median anti-SARS-CoV-2 IgG binding titers were 8.6-fold lower in NHL/CLL patients without prior SARS-CoV-2 infections compared to healthy individuals. IgA and IgM titers were similarly reduced. Among the 51 patients with available pre- and post-booster samples, only 45% achieved a >3.16 fold-increase in IgG titers after booster (median fold increase = 2.58 vs 41.0 for healthy vaccinees). A substantial decrease in IgG binding to variant SARS-CoV-2 spike, particularly from B.1.1.529 (Omicron) variants, was observed. However, reductions were similar to healthy vaccinees (median fold reduction: 4.82 vs 4.83, respectively). Neutralizing antibody titers against WA1/2020 strain were detected in 44% of patients but only 16% of patients had neutralizing antibody titers against Omicron before booster vaccination. Neutralizing titers against WA1/2020 and Omicron were detected in 61% and 43% of patients after booster respectively, though mean titers against Omicron were 11.5-fold lower than WA1/2020. Clinical correlates to vaccine response including treatment status will be presented. Conclusions: Antibody binding and live-virus neutralization titers against SARS-CoV-2 and its variants including Omicron are lower in NHL/CLL patients compared to healthy individuals even after booster vaccination. Our study reinforces the need to prioritize anti-SARS-CoV-2 prophylactic and treatment agents to protect this highly immunosuppressed population. Funding: Winship Cancer Institute and Emory University Institutional Funds, NCI U54 CA260563, P30CA138292, NIH P51 OD011132, HHSN272201400004C, U19AI090023, R35CA197603.

Lower limb ulcer and Raynaud's phenomenon

A 64-year -old patient sought medical advice for an ulcer of the lower extremities (Fig 1). He also presented with claudication, chronic dyspnea, skin thickening, and late-onset Raynaud's phenomenon (RP). There were no palpable dorsalis pedis or posterior tibial pulses. Skin examination showed reduction of forehead folds, facial and tongue telangiectasias, xerosis cutis, salt-and-pepper hyperpigmentation, sclerodactyly, digital ulcerations, and pitting scars (Fig 2). Chest auscultation revealed crackles on the lower lobes.

Early expression of CD94 and loss of CD96 on CD8+ T cells after allogeneic stem cell tranplantation is predictive of subsequent relapse and survival.

Allogeneic stem cell transplantation is used widely in the treatment of hematopoietic malignancy. However, relapse of malignant disease is the primary cause of treatment failure and reflects loss of immunological graft-versus-leukemia effect. We studied the transcriptional and phenotypic profile of CD8+ T cells in the first month following transplantation and related this to risk of subsequent relapse. Single cell transcriptional profiling identified five discrete CD8+ T-cell clusters. High levels of T-cell activation and acquisition of a regulatory transcriptome were apparent in patients who went on to suffer disease relapse. A relapse-associated gene signature of 47 genes was then assessed in a confirmation cohort of 34 patients. High expression of the inhibitory receptor CD94/NKG2A on CD8+ T cells within the first month was associated with 4.8 fold increased risk of relapse and 2.7 fold reduction in survival. Furthermore, reduced expression of the activatory molecule CD96 was associated with 2.2 fold increased risk of relapse and 1.9 fold reduction in survival. This work identifies CD94 and CD96 as potential targets for CD8-directed immunotherapy in the very early phase following allogeneic transplantation with the potential to reduce long term relapse rates and improve patient survival.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

The beneficial effect of Pluchea lanceolata on aluminum chloride-induced Alzheimer's disease in rats

Aluminum chloride (AlCl3) causes neuroinflammation in rats, which leads to the development of Alzheimer's disease. The current study focused on the anti-Alzheimer and antioxidant potential of hydromethanolic extracts of Pluchea lanceolata (PL), a well-known Rasna source. Phytoconstituents such as pluchine and moretenol acetate are selected for the PASS online and molecular docking (in silico) experimental model. A total of 36 Wistar rats were divided into VI groups, each with six rats. Group I: normal control, Group II: disease control, Group III: Rivastigmine (0.3 mg/kg, p.o), Group IV and V: Hydromethanolic extract of PL (HMEPL, 200 mg/kg, 400 mg/kg, p.o), and Group VI: Ayurvedic Formulation of Rasna (AFR) (1ml/kg, p.o). Except for group I, all of the animals were given Aluminum Chloride (AlCl3) (300 mg/kg, p.o). AlCl3 and plant extracts were given for 20day treatment. On the 0th, 7th, 14th, and 20th days, the behavioural study and changes in body weight were evaluated. Rats were sacrificed on the 21st day, their brains were separated, and antioxidant enzyme levels, protein levels, and neurotransmitter levels were measured. Histopathologies of the cortex and hippocampus parts of the brain were studied. The number of entries, as well as time spent in the closed arm and time taken to ascend the pole, were all increased in Group II animals, but this was reversed in groups treated with 200 mg/kg, 400 mg/kg, and1 ml/kg dosages of HMEPL and AFR. In the disease control group, AlCl3 (300 mg/kg, p.o.) caused a 1.5 fold increase in protein content and 1.7 fold increase in malondialdehyde, similarly, 1.3 fold reduction in body weight, 2.2 fold superoxide dismutase, 3.3 fold catalase, and 3.1 fold glutathione level were observed and were corrected and restored in groups treated with HMEPL and AFR. Furthermore, the histopathology findings revealed that HMEPL and AFR provided the cellular-level protection. The active components of HMEPL were found to have anti-Alzheimer and antioxidant potential and were confirmed in an in silico investigation. HMEPL &amp;gt; AFR was the order of anti-Alzheimer and antioxidant effectiveness.

Quantitative Assessment of the Impact of Crohn's Disease on Protein Abundance of Human Intestinal Drug-Metabolising Enzymes and Transporters

Crohn's disease affects the mucosal layer of the intestine, predominantly ileum and colon segments, with the potential to affect the expression of intestinal enzymes and transporters, and consequently, oral drug bioavailability. We carried out a quantitative proteomic analysis of inflamed and non-inflamed ileum and colon tissues from Crohn's disease patients and healthy donors. Homogenates from samples in each group were pooled and protein abundance determined by liquid chromatography–mass spectrometry (LC-MS). In inflamed Crohn's ileum, CYP3A4, CYP20A1, CYP51A1, ADH1B, ALPI, FOM1, SULT1A2, SULT1B1 and ABCB7 showed ≥10-fold reduction in abundance compared with healthy baseline. By contrast, only MGST1 showed ≥10 fold reduction in inflamed colon. Ileal UGT1A1, MGST1, MGST2, and MAOA levels increased by ≥2 fold in Crohn's patients, while only ALPI showed ≥2 fold increase in the colon. Counter-intuitively, non-inflamed ileum had a higher magnitude of fold change than inflamed tissue when compared with healthy tissue. Marked but non-uniform alterations were observed in the expression of various enzymes and transporters in ileum and colon compared with healthy samples. Modelling will allow improved understanding of the variable effects of Crohn's disease on bioavailability of orally administered drugs.

Nomenclature and Definition of Atrophic Lesions in Small Bowel Capsule Endoscopy: A Delphi Consensus Statement of the International CApsule endoscopy REsearch (I-CARE) Group.

(1) Background: Villous atrophy is an indication for small bowel capsule endoscopy (SBCE). However, SBCE findings are not described uniformly and atrophic features are sometimes not recognized; (2) Methods: The Delphi technique was employed to reach agreement among a panel of SBCE experts. The nomenclature and definitions of SBCE lesions suggesting the presence of atrophy were decided in a core group of 10 experts. Four images of each lesion were chosen from a large SBCE database and agreement on the correspondence between the picture and the definition was evaluated using the Delphi method in a broadened group of 36 experts. All images corresponded to histologically proven mucosal atrophy; (3) Results: Four types of atrophic lesions were identified: mosaicism, scalloping, folds reduction, and granular mucosa. The core group succeeded in reaching agreement on the nomenclature and the descriptions of these items. Consensus in matching the agreed definitions for the proposed set of images was met for mosaicism (88.9% in the first round), scalloping (97.2% in the first round), and folds reduction (94.4% in the first round), but granular mucosa failed to achieve consensus (75.0% in the third round); (4) Conclusions: Consensus among SBCE experts on atrophic lesions was met for the first time. Mosaicism, scalloping, and folds reduction are the most reliable signs, while the description of granular mucosa remains uncertain.

Use of tranexamic acid in per trochanteric fractures: Is it beneficial?

Background: Elderly people who have hip fractures frequently need blood transfusions. The purpose of this study was to ascertain whether tranexamic acid (TXA) usage in hip fracture patients lowers intraoperative and postoperative blood loss. For a year, patients with hip fractures were the subjects of the study. Two groups of patients were formed, with one getting TXA and the other receiving a placebo (1:1). Both the amount of drainage during the 48-hour postoperative period and the amount of blood lost during the procedure were measured. Patients who received TXA experienced a 1.4 fold reduction in total blood loss (368.61 vs.529.24 mL of blood). Thus the use of TXA in patients with per trochanteric fractures significantly reduces intraoperative and postoperative blood loss.

SERINC5 Restricts HIV-1 Infectivity by Promoting Conformational Changes and Accelerating Functional Inactivation of Env.

SERINC5 incorporates into HIV-1 particles and inhibits the ability of Env glycoprotein to mediate virus-cell fusion. SERINC5-resistance maps to Env, with primary isolates generally showing greater resistance than laboratory-adapted strains. Here, we examined a relationship between the inhibition of HIV-1 infectivity and the rate of Env inactivation using a panel of SERINC5-resistant and -sensitive HIV-1 Envs. SERINC5 incorporation into pseudoviruses resulted in a faster inactivation of sensitive compared to resistant Env strains. A correlation between fold reduction in infectivity and the rate of inactivation was also observed for multiple Env mutants known to stabilize and destabilize the closed Env structure. Unexpectedly, most mutations disfavoring the closed Env conformation rendered HIV-1 less sensitive to SERINC5. In contrast, functional inactivation of SERINC5-containing viruses was significantly accelerated in the presence of a CD4-mimetic compound, suggesting that CD4 binding sensitizes Env to SERINC5. Using a small molecule inhibitor that selectively targets the closed Env structure, we found that, surprisingly, SERINC5 increases the potency of this compound against a laboratory-adapted Env which prefers a partially open conformation, indicating that SERINC5 may stabilize the closed trimeric Env structure. Our results reveal a complex effect of SERINC5 on Env conformational dynamics that promotes Env inactivation and is likely responsible for the observed restriction phenotype.

PB2270: CLEARANCE OF PERSISTENT SARS-COV2 INFECTION WITH ANTIBODY CONTAINING PLASMA IN LEUKEMIA AND LYMPHOMA PATIENTS

Background: Patients with hematological malignancies or other reasons for inadequate immune response are at high risk for poor outcome of COVID-19 disease. In addition, a significant fraction of patients unable to mount an antibody response fail to clear SARS-Cov2 virus putting them at risk for clinical deterioration. Also, persistent COVID-19 infection impedes further treatment of the underlying disease. So far, no treatment has been established for persistent COVID-19 infection in immunocompromised patients. Aims: Here, we treated eight immunocompromised patients with active SARS-COV2 infection with plasma from convalescent or/and vaccinated donors in a case series of individual treatments. Methods: Patients were eligible for treatment if active SARS-Cov2 infection was confirmed at least 14 days after initial detection. In two out of eight patients sequencing results confirmed the omicron variant. Therapies before plasma treatment included antivirals and monoclonal antibodies. Underlying diseases were B-ALL (n=3; including one patient after allogeneic stem cell transplantation), multiple myeloma (n=2), lymphoma (n=2) and immunosuppression after kidney transplantation (n=1). Median age was 48 years (range 7 – 78). Antibody containing plasma was obtained from healthy donors either after confirmed SARS-COV2 infection or after mRNA vaccination. Overall, 22 treatment cycles were administered in 8 patients (median 2, range 1 to 7). For each patient the available plasma with the highest titers of neutralizing antibodies and matching blood type was administered. Results: Neutralizing antibody titers in plasma were median 1:320 (range 1:40 to 1:2560). Titers of neutralizing antibodies in convalescent plasma (n=10 treatments; median titer: 1:80) were lower than in vaccinated donor plasma (median 1:320; p=0.058, Mann-Whitney U test) (n=12 treatments). Median Ct-values of viral load before treatment were 20.5 (range 14.9 to 37.3). After treatment (median 5 days), the Ct-values changed to median 26.9 (range 19.5 to non-detectable). The median fold decrease in viral load was estimated to be 127-fold with a range from 0.8 to >2x104 (p<10-4, paired t-test). Similar reductions in viral load were achieved after administration of either plasma from convalescent (median 109) or vaccinated donors. SARS-COV2 virus was cleared in 7 of 8 (87.5%) patients with ongoing treatment in one patient. No specific adverse events were observed. Figure 1: Fold reduction in viral load after a single treatment with anti-SARS-COV2 containing plasma. Image:Summary/Conclusion: Plasma with high titers of neutralizing SARS-COV2 antibodies can clear persistent infection in patients with hematological malignancies and immunocompromised patients. Plasma obtained either from convalescent patients or vaccinated donors might constitute an effective and inexpensive treatment in this situation.