Immunogenicity of a peptide-based vaccine for measles: a pilot evaluation in a mouse model.

Although neutralizing antibody is an established correlate of protection for measles, T cell-mediated responses play at least two critical roles in immunity to measles: first, through provision of 'help' enabling robust humoral immune responses; and second, through clearance of measles virus-infected cells. Previously, we identified 13 measles-derived peptides that bound to human leukocyte antigen (HLA) molecules in Priess cells infected with measles virus. In this study, we evaluated the immunogenicity of these peptides in a transgenic mouse model. Our results demonstrated that these peptides induced Th1-biased immune responses at varying levels. Of the 13 peptides, the top four immunogenic peptides were further selected for a viral challenge study in mice. A vaccine based on a combination of these four peptides reduced morbidity and weight loss after viral challenge compared to placebo. Our results emphasize the potential of T cell-mediated, peptide-based vaccines against measles.

Ruthenium drug BOLD-100 regulates BRAFMT colorectal cancer cell apoptosis through AhR/ROS/ATR signaling axis modulation.

Patients with class I V600EBRAF-mutant (MT) colorectal cancer (CRC) have a poor prognosis and their response to combined anti-BRAF/EGFR inhibition remains limited. There is clearly an unmet need in further understanding the biology of V600EBRAFMT CRC. We have used differential gene expression of BRAFWT and MT CRC cells to identify pathways underpinning BRAFMT CRC. We tested a panel of molecularly/genetically subtyped CRC cells for their sensitivity to the Unfolded Protein Response (UPR) activator BOLD-100. To identify novel combination strategies for BOLD-100, we performed RNA sequencing and high-throughput drug screening. Pathway enrichment analysis identified that the UPR and DNA repair pathways were significantly enriched in BRAFMT CRC. We found that oncogenic BRAF plays a crucial role in mediating response to BOLD-100. Using a systems biology approach, we identified V600EBRAFMT-dependent activation of the replication stress response kinase ATR as a key mediator of resistance to BOLD-100. Further analysis identified acute increases in BRAFMT-dependent-reactive oxygen species (ROS) levels following treatment with BOLD-100 that was demonstrated to promote ATR/CHK1 activation and apoptosis. Furthermore, activation of ROS/ATR/CHK1 following BOLD-100 was found to be mediated through the AHR transcription factor and CYP1A1. Importantly, pharmacological blockade of this resistance pathway with ATR inhibitors synergistically increased BOLD-100-induced apoptosis and growth inhibition in BRAFMT models. These results unveil possible novel therapeutic opportunity for BRAFMT CRC. Implications: BOLD-100 induces BRAFMT-dependent replication stress, and targeted strategies against replication stress (eg. by using ATR inhibitors) in combination with BOLD-100 may serve as a potential novel therapeutic strategy for clinically aggressive BRAFMT CRC.

Application of the Symptoms-Varices-Pathophysiology classification system in patients with pelvic venous disorders.

Introduction: In 2021, the American Vein and Lymphatic Society convened a multi-disciplinary group to develop a valid and reliable discriminative instrument for the classification of patients suffering from pelvic venous disorders (PeVD) referred to as the Symptoms-Varices-Pathophysiology (SVP) system. Limited data exists regarding the utility of this instrument in the care of patients with PeVD. The goal of this investigation is to apply the SVP classification system to a group of patients treated for PeVDs. Methods: From January 2018 to January 2019, we retrospectively reviewed the records of 70 female patients treated for a PeVD at the Center for Vascular Medicine. Age, race, gender, medical/surgical histories, CEAP classification and intervention types were assessed and patients were categorized according to their SVP classification. The prevalence of each S and V class, their association with gonadal or iliac vein obstructive lesions and the prevalence of lower extremity varicosities was evaluated. Results: The average age of the entire cohort was 47.4 ± 13.4. The race distribution was as follows: African American (6), Hispanic (1), and Caucasian (63). Of the 140 limbs, 57% were C3 or greater with an average rVCSS score of 4.53. At the time of intervention, 54 patients (77%) demonstrated CEAP class 2 disease or greater with 25 patients (35%) demonstrating lower extremity varicosities. Medical co-morbidities included the following: Endometriosis (n = 1), Uterine Fibroids (n = 1), Ovarian cysts (n = 4), history of venous thrombosis (n = 2) and prior lower extremity venous procedures (n = 3). Overall, 47 patients (67.1%) demonstrated S2 disease secondary to dyspareunia, post-coital pain, or dysmenorrhea. S2 alone was observed in 17 patients (24.3%), S2,3a and S2,3a,3b in nine patients each (12.9%), and S2,3b was in 12 patients (17.1%). Thirteen patients presented with isolated extra-pelvic symptoms (19%); four (5.7%) were classified as S3a,3b, and nine (12.9%) were classified as S3b only. Finally, 10 patients (14%) had no pelvic symptoms and thus were classified as S0. V0 disease was observed in 17 patients (24.3%) secondary to a high incidence of iliac vein stenoses (IVS). V1 disease was observed in 1 patient (1.43%). V2 disease was observed in 53 patients (74.3%) secondary to iliac or ovarian vein reflux. Of these, 45 patients (64.3%) presented with reflux in the iliac veins. Sixteen patients had reflux in the common iliac veins, 17 patients exhibited reflux of the external iliac veins, and 41 patients demonstrated reflux of the internal iliac veins. Thirty-two patients (45.7%) presented with V2 disease secondary to reflux of the ovarian veins, 8 of whom presented with isolated ovarian vein reflux without IVS. Bilateral ovarian vein reflux was observed in 6 patients (9%) and unilaterally in 26 (37%) patients with concomitant ovarian vein reflux and IVS observed in 31 patients (44%). In patients with ovarian vein reflux, 89% had a concomitant iliac vein stenosis: (96.9% in the common iliac vein, 81.3% in the external iliac vein and 3.1% in the internal iliac vein). Conclusion: In our patient cohort, 70 women demonstrated 14 different SV classifications. The most common was S2V2, found in 10 patients. Chronic pelvic pain of venous origin, S2 disease, was the most common symptom, present in 47 patients (67.1%); followed by extra-pelvic symptoms as 22 patients demonstrated symptoms of the external genitalia (S3a), and 21 patients had symptoms secondary to the non-saphenous leg veins (S3b). Pelvic varicosities, V2, were also the most common variceal pattern seen in 53 patients, and 17 patients did not have any varices noted by venogram. Non-thrombotic IVS either alone or with ovarian vein reflux was the most common cause of PeVD in this cohort and may reflect referral patterns to our center. To determine the true incidence of these SVP patterns, larger cohort studies are necessary.

USP7 inhibitors suppress tumour neoangiogenesis and promote synergy with immune checkpoint inhibitors by downregulating fibroblast VEGF.

BACKGROUND: Understanding how to modulate the microenvironment of tumors that are resistant to immune checkpoint inhibitors represents a major challenge in oncology.Here we investigate the ability of USP7 inhibitors to reprogram the tumor microenvironment (TME) by inhibiting secretion of vascular endothelial growth factor (VEGF) from fibroblasts. METHODS: To understand the role played by USP7 in the TME, we systematically evaluated the effects of potent, selective USP7 inhibitors on co-cultures comprising components of the TME, using human primary cells. We also evaluated the effects of USP7 inhibition on tumor growth inhibition in syngeneic models when dosed in combination with immune checkpoint inhibitors (ICIs). RESULTS: Abrogation of VEGF secretion from fibroblasts in response to USP7 inhibition resulted in inhibition of tumor neoangiogenesis and increased tumor recruitment of CD8-positive T-lymphocytes, leading to significantly improved sensitivity to immune checkpoint inhibitors. In syngeneic models, treatment with USP7 inhibitors led to striking tumor responses resulting in significantly improved survival. CONCLUSIONS: USP7-mediated reprograming of the TME is not linked to its previously characterized role in modulating MDM2 but does require p53 and UHRF1 in addition to the well-characterized VEGF transcription factor, HIF-1α. This represents a function of USP7 that is unique to fibroblasts, and which is not observed in cancer cells or other components of the TME. Given the potential for USP7 inhibitors to transform "immune desert" tumors into "immune responsive" tumors, this paves the way for a novel therapeutic strategy combining USP7 inhibitors with immune checkpoint inhibitors (ICIs).

Detection of SARS-CoV-2-Specific Cells Utilizing Whole Proteins and/or Peptides in Human PBMCs Using IFN-Æ´ ELISPOT Assay.

SARS-CoV-2 continues to threaten global public health, making COVID-19 immunity studies of utmost importance. Waning of antibody responses postinfection and/or vaccination and the emergence of immune escape variants have been ongoing challenges in mitigating SARS-CoV-2 morbidity and mortality. While a tremendous amount of work has been done to characterize humoral immune responses to SARS-CoV-2 virus and vaccines, cellular immunity, mediated by T cells, is critical for efficient viral control and protection and demonstrates high durability and cross-reactivity to coronavirus variants. Thus, ELISPOT, a standard assay for antigen-specific cellular immune response assessment, allows us to evaluate SARS-CoV-2-specific T-cell response by quantifying the frequency of SARS-CoV-2-specific cytokine-secreting cells in vitro. We have outlined a detailed procedure to study T-cell recall responses to SARS-CoV-2 in human peripheral blood mononuclear cells (PBMCs) following infection and/or vaccination using an optimized IFN-γ ELISPOT assay. Our methodologies can be adapted to assess other cytokines and are a useful tool for studying other viral pathogen and/or peptide-specific T-cell responses.

Restricted life-space mobility impacts physical but not mental quality of life in older cancer survivors.

BACKGROUND: Older cancer survivors often value quality of life (QOL) over survival. Life-space mobility (LSM), defined as the individual's spatial geographic mobility range, is an important QOL indicator in older adults with chronic illnesses; however, this relationship is unexplored in older cancer survivors. METHODS: We examined the longitudinal associations and causal relationships between LSM and QOL in 153 older cancer survivors (≥65 years) from the University of Alabama at Birmingham (UAB) Study of Aging. LSM was assessed using the UAB Life-Space Assessment-Composite score (LSA-C), and QOL was assessed by the SF-12 Mental Component Score (MCS12) and Physical Component Score (PCS12) at 0 (study entry), 6, 18, 36, 54, and 72 months. We examined the causal relationship between LSM and QOL using a cross-lagged panel model (CLPM). RESULTS: The cohort (n = 153) was 76 years old on average and predominantly White (58%), female (58%), and married (55%). Longitudinal analyses found LSM decreased over time (p < 0.0001), and this decrease was associated with decreased QOL (PCS12, p < 0.0001, MCS12, p < 0.0001). In the CLPM causal analysis, lower LSM resulted in worse PCS12 (p < 0.001), but not worse MSC12. CONCLUSIONS: Restricted LSM resulted in worse physical QOL over 72 months in a sample of 153 older cancer survivors. Developing and evaluating interventions to preserve greater LSM could be a promising approach to improving QOL.

A multifaceted approach for identification, validation, and immunogenicity of naturally processed and in silico-predicted highly conserved SARS-CoV-2 peptides.

SARS-CoV-2 remains a major global public health concern. Antibody waning and immune escape variant emergence necessitate the development of next generation vaccines that induce cross-reactive durable immune responses. T cell responses to SARS-CoV-2 demonstrate higher conservation, antigenic breadth, and longevity than antibody responses. Therefore, we sought to identify pathogen-derived T cell epitopes for a potential peptide-based vaccine. We pursued an approach leveraging: 1) liquid chromatography and tandem mass spectrometry (LC-MS/MS)-based identification of peptides from ancestral SARS-CoV-2-infected cell lines, 2) epitope prediction algorithms, and 3) overlapping peptide libraries. From this strategy, we identified 380 unique SARS-CoV-2-derived peptide sequences, including 53 antigenic HLA class I and class II peptides from multiple structural and non-structural/accessory viral proteins. These peptide sequences were highly conserved across variants of concern/interest (VoC/VoIs), and are estimated to achieve coverage of >96% of the world population. Our findings validate this discovery pipeline for peptide identification and immunogenicity testing, and are a crucial step toward the development of a next-generation multi-epitope SARS-CoV-2 peptide vaccine, and a novel vaccine platform methodology.

Dual Prognostic Classification of Triple-Negative Breast Cancer by DNA Damage Immune Response and Homologous Recombination Deficiency.

PURPOSE: Triple-negative breast cancer (TNBC) is a heterogeneous disease. We previously showed that homologous recombination deficiency (HRD) and the DNA damage immune response (DDIR) signature are prognostic in TNBC. We hypothesized that these biomarkers reflect related but not completely interdependent biological processes, that their combined use would be prognostic, and that simultaneous assessment of the immunologic microenvironment and susceptibility to DNA damaging therapies might be able to identify subgroups with distinct therapeutic vulnerabilities. METHODS: We analyzed the dual DDIR/HRD classification in 341 patients with TNBC treated with adjuvant anthracycline-based chemotherapy on the SWOG S9313 trial and corroborated our findings in The Cancer Genome Atlas breast cancer data set. RESULTS: DDIR/HRD classification is highly prognostic in TNBC and identifies biologically and immunologically distinct subgroups. Immune-enriched DDIR+/HRD+ TNBCs have the most favorable prognosis, and DDIR+/HRD- and DDIR-/HRD+ TNBCs have favorable intermediate prognosis, despite the latter being immune-depleted. DDIR-/HRD- TNBCs have the worst prognosis and represent an internally heterogeneous group of immune-depleted chemoresistant tumors. CONCLUSION: Our findings propose DDIR/HRD classification as a potentially clinically relevant approach to categorize tumors on the basis of therapeutic vulnerabilities.

Genome-wide determinants of cellular immune responses to mumps vaccine.

BACKGROUND: We have previously described genetic polymorphisms in candidate genes that are associated with inter-individual variations in antibody responses to mumps vaccination. To expand upon our previous work, we performed a genome-wide association study (GWAS) to discover host genetic variants associated with mumps vaccine-induced cellular immune responses. METHODS: We performed a GWAS of mumps-specific immune response outcomes (11 secreted cytokines/chemokines) in a cohort of 1,406 subjects. RESULTS: Among the 11 cytokine/chemokines we studied, four (IFN-γ, IL-2, IL-1ß, and TNFα) demonstrated GWAS signals reaching genome-wide significance (p < 5 × 10-8). A genomic region (encoding Sialic acid-binding immunoglobulin-type lectins/SIGLEC) located on chromosome 19q13 (p < 5 × 10-8) was associated with both IL-1ß and TNFα responses. The SIGLEC5/SIGLEC14 region contained 11 statistically significant single nucleotide polymorphisms (SNPs), including the intronic SIGLEC5 rs872629 (p = 1.3E-11) and rs1106476 (p = 1.32E-11) whose alternate alleles were significantly associated with decreased levels of mumps-specific IL-1ß (rs872629, p = 1.77E-09; rs1106476, p = 1.78E-09) and TNFα (rs872629, p = 1.3E-11; rs1106476, p = 1.32E-11) production. CONCLUSIONS: Our results suggest that SNPs in the SIGLEC5/SIGLEC14 genes play a role in cellular and inflammatory immune responses to mumps vaccination. These findings motivate further research into the functional roles of SIGLEC genes in the regulation of mumps vaccine-induced immunity.

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

Integrated Multimodal Analyses of DNA Damage Response and Immune Markers as Predictors of Response in Metastatic Triple-Negative Breast Cancer in the TNT Trial (NCT00532727).

PURPOSE: The TNT trial (NCT00532727) showed no evidence of carboplatin superiority over docetaxel in metastatic triple-negative breast cancer (mTNBC), but carboplatin benefit was observed in the germline BRCA1/2 mutation subgroup. Broader response-predictive biomarkers are needed. We explored the predictive ability of DNA damage response (DDR) and immune markers. EXPERIMENTAL DESIGN: Tumor-infiltrating lymphocytes were evaluated for 222 of 376 patients. Primary tumors (PT) from 186 TNT participants (13 matched recurrences) were profiled using total RNA sequencing. Four transcriptional DDR-related and 25 immune-related signatures were evaluated. We assessed their association with objective response rate (ORR) and progression-free survival (PFS). Conditional inference forest clustering was applied to integrate multimodal data. The biology of subgroups was characterized by 693 gene expression modules and other markers. RESULTS: Transcriptional DDR-related biomarkers were not predictive of ORR to either treatment overall. Changes from PT to recurrence were demonstrated; in chemotherapy-naïve patients, transcriptional DDR markers separated carboplatin responders from nonresponders (P values = 0.017; 0.046). High immune infiltration was associated with docetaxel ORR (interaction P values < 0.05). Six subgroups were identified; the immune-enriched cluster had preferential docetaxel response [62.5% (D) vs. 29.4% (C); P = 0.016]. The immune-depleted cluster had preferential carboplatin response [8.0% (D) vs. 40.0% (C); P = 0.011]. DDR-related subgroups were too small to assess ORR. CONCLUSIONS: High immune features predict docetaxel response, and high DDR signature scores predict carboplatin response in treatment-naïve mTNBC. Integrating multimodal DDR and immune-related markers identifies subgroups with differential treatment sensitivity. Treatment options for patients with immune-low and DDR-proficient tumors remains an outstanding need. Caution is needed using PT-derived transcriptional signatures to direct treatment in mTNBC, particularly DDR-related markers following prior chemotherapy.

Transabdominal ultrasound accurately identifies a significant iliac vein area-reducing lesion in patients with pelvic venous insufficiency.

BACKGROUND: In patients with pelvic venous disorders secondary to pelvic venous insufficiency (PVI), the optimal imaging modality is ill-defined. Transabdominal ultrasound (TAU) is widely used to identify the presence of iliac vein stenosis. The purpose of the present investigation is to determine the accuracy of TAU for determining the presence of an iliac vein area-reducing lesion compared with intravascular ultrasound (IVUS). METHODS: From January to December 2020, a retrospective review of prospectively collected data from 96 patients treated for symptomatic PVI at the Center for Vascular Medicine was performed. All patients had complete history and physical examination findings, demographics, CEAP (clinical, etiologic, anatomic, pathophysiologic), revised venous clinical severity score, and TAU, diagnostic venography, and IVUS measurements recorded in our electronic medical record system. All TAU measurements were performed by the same ultrasound technician with the patient in the supine position. Iliac vein diameters of the common femoral, external iliac, and common iliac veins and the inferior vena cava were obtained. Differences in body habitus were normalized by dividing the minimum diameter measurement of the stenotic vessel with that of the ipsilateral common femoral vein, subtracting this number from 1 and multiplying by 100 (stenosis = [1 - minimal diameter/common femoral diameter] × 100). The normalized stenoses were then compared with the IVUS-derived area reducing measurements. A receiver operating characteristic curve was created, and logistic regression analysis for the probability of predicting an area-reducing lesion of >50% and >60% with TAU was performed. The sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: The average age of the entire cohort was 49.8 ± 13.5 years, with 69 women and 27 men. The CEAP distribution was as follows: C0, 5%; C1, 5%; C2, 10%; C3, 40%; C4a,b, 30%; C5, 7%; and C6, 3%. The average revised venous clinical severity score was 6.2 ± 2.6. The indications for intervention were leg symptoms alone in 43%, pelvic symptoms alone in 3%, and combined leg and pelvic symptoms in 54%. TAU identified a stenosis of ≥50% in 92 of the 96 patients (96%). For a ≥50% stenosis, a normalized diameter of ≤3 mm demonstrated a sensitivity, specificity, and positive and negative predictive value of 75%, 75%, 98%, and 12%, respectively. Logistic regression analysis indicated that TAU was significant in predicting the presence of a ≥60% area-reducing lesion (odds ratio, 1.03; 95% confidence interval, 1.01-1.05; P = .009). The area under the receiver operating characteristic curve (c-statistic) was 68.6%. The sensitivity, specificity, and positive and negative predictive values were 66.7%, 66.7%, 81.5%, and 47.6%, respectively, for a normalized diameter of ≥4 mm. CONCLUSIONS: The ability of TAU to identify an iliac vein stenosis of ≥50% is 96%. The positive predictive value for TAU to identify a ≥60% iliac vein area-reducing lesion is high, with moderate sensitivity and specificity. For patients with symptoms consistent with pelvic venous disorders secondary to PVI, TAU is a good preintervention screening modality for properly trained vascular imaging specialists with findings that correlate well with IVUS measurements.

Natural history and role of anticoagulation in the management of endovenous glue-induced thrombus.

OBJECTIVE: The natural history of endovenous glue-induced thrombus (EGIT) resolution and the role of anticoagulation (AC) and/or anti-platelet (AP) agents in their management is currently ill-defined. The goal of this investigation is to determine the clinical behavior of EGITs and whether or not AC or AP affects treatment outcomes. METHODS: We performed a retrospective review of all endovenous ablations utilizing cyanoacrylate glue (CAG) from January 2020 to December 2021 at the Center for Vein Restoration. Patients were divided into two groups: (1) patients who developed an EGIT (EGIT/CAG) and (2) patients treated with CAG and no EGIT development (CAG). Demographics, medical/surgical histories, revised Venous Clinical Severity Score (rVCSS), Chronic Venous Insufficiency Quality of Life Questionnaire (CIVIQ), CEAP, EGIT category, type of anticoagulation, resolution time, location of any deep vein thrombosis (DVT) were analyzed, catheter tip distance, treatment length and proximal thigh diameters were all analyzed. EGITs were categorized as follows: EGIT 1: thrombus extension into the deep vein covering less than 25% of the luminal area; EGIT 2: thrombus between 25% and 49%; EGIT 3: thrombus between 50% and 74%; and EGIT 4: total occlusion. Our protocol is to perform post-procedure duplex scans within 3 to 7 days after endovenous ablations to assess for post-intervention DVTs. RESULTS: During the study period, 2374 patients received 4321 CAG procedures. EGITs were observed in 133 patients (3.1%): EGIT 1 (n = 57); EGIT 2 (n = 35); EGIT 3 (n = 19); and EGIT 4 (n = 22). All EGITs were identified by surveillance scanning. No patient presented with limb or pulmonary symptoms suggestive of VTE. The average age, rVCSS, and CIVIQ 20 of the entire cohort was 65.3 ± 14.2 years, 8.2 ± 2.8, and 48 ± 18.3, respectively with 89 females and 44 males. For EGIT 1, 56 of 57 (98%) resolved at 4.2 ± 5.1 weeks, with one patient lost to follow-up. AC/AP regimen included two aspirin (ASA), one Eliquis, 5 Xarelto, and nothing in 49 patients (86%). For EGIT 2, 27 of 35 (77%) resolved at 4.4 ± 3.4 weeks, one was unresolved, six regressed to EGIT 1, and one remained an EGIT 2 at the last follow-up examination. AC/AP regimens included seven ASA, three Eliquis, three Xarelto, one Coumadin, and nothing in 21 patients (60%). For EGIT 3, 12 were in the common femoral vein (CFV), three in the popliteal vein (POPV), one in the external iliac vein, and three in the gastrocnemius veins. Nine of nineteen (47%) resolved at 6 ± 5.9 weeks, four regressed, one migrated to the proximal CFV, three became chronic, and two were lost to follow-up. AC/AP regimens included three ASA, three Eliquis, seven Xarelto, and nothing in six patients (32%). AC/AP compared with no AC/AP had no effect on clot resolution (P = .3). Of the 22 EGIT 4, one was in the CFV, two were in the POPV, and 18 (82%) were remote calf vein DVTs (15 gastrocnemius, one peroneal [PV], and three posterior tibial veins [PTVs]). The CFV EGIT became chronic, one POPV resolved, and one was lost to follow-up. For the gastrocnemius clots, five became chronic, eight resolved, and two were lost to follow-up. For the PTV clots, one resolved, one became chronic, and one was lost to follow-up. The PV clot became chronic. AC/AP regimen included four ASA, five Eliquis, six Xarelto, and nothing in seven patients. AC/AP compared with no AC/AP had no effect on clot resolution (P = .9). The average proximal thigh diameter (millimeters, mm), vein length treated (mm), and catheter distance (mm) from the junction were the following: EGIT 1 (5.9 ± 2.4, 37.5 ± 17.6, and 5.2 ± 1), EGIT 2 (5.9 ± 1.7, 38 ± 16.9, 4.79 ± 0.71), EGIT 3 (5.1 ± 2.6, 27.9 ± 16.6, and 5.26 ± 1.4), and EGIT 4 (5 ± 1.7, 29.9 ± 15.8, and 5.39 ± 2.18), respectively. Treatment length alone was significantly shorter in EGIT 3 and 4, compared with EGIT 1 and 2 (P ≤ .05). Catheter distance from the junction was longer in EGIT 1, 3, and 4 patients compared with CAG patients (P ≤ .02). CONCLUSIONS: Regardless of EGIT class or severity, the majority of EGITs are not associated with clot extension or migration and tend to resolve or regress. For EGIT class 1 and 2 patients, AC or AP therapy is not necessary, as 86% and 60%, respectively, resolved with observation alone by 4 weeks. For EGIT 3, 68% resolved or regressed regardless of AC or AP use. The majority of EGIT 4 were remote calf vein DVTs. EGIT 3 and 4 associated with the saphenofemoral/popliteal junction are rare. When compared with CAG patients, proximal thigh diameters and treatment lengths were larger and longer in EGIT 1 and 2 patients. Catheter proximity to the junction was not associated with a higher incidence of EGIT formation.

Functional humoral and cellular response of monovalent COVID-19-vaccines against Omicron BA.2 variant of SARS-CoV-2 in patients with chronic lymphocytic leukemia.

We designed a prospective study to evaluate the humoral (using a surrogate virus neutralization test) and cellular (using an IFN-γ ELISpot) immune response among patients with chronic lymphocytic leukemia (CLL) against Wuhan-Hu-1 and Omicron BA.2 strains of SARS-CoV-2, after mRNA-based vaccination. The proportion of patients with a functional humoral response was higher among untreated CLL patients compared to treated CLL patients against both Wuhan-Hu-1 and Omicron BA.2 after the second and the third dose of vaccination, and at 12 months after the first dose. The proportion of positive cellular response against the peptide pool covering the full-length Wuhan-Hu-1 spike protein was similar between untreated and treated CLL patients at all three timepoints. The cellular response to the mutated regions of BA.2 spike protein was lower than the response to the corresponding regions in the ancestral spike after the second dose, but this difference was eliminated after the third dose.

A practice audit of short-term outcomes of Wallstents versus Venovo stents for the treatment of nonthrombotic iliac vein outflow stenoses.

OBJECTIVE: The Wallstent (WS; Boston Scientific, Malborough, MA) is currently the standard of care for comparisons of clinical efficacy for new stent devices in the treatment of iliac vein outflow disease. Many vein-specific Nitinol-based stents have been now approved by the Food and Drug Administration for use in the iliofemoral venous system. However, few comparisons of these devices to the current standard have been reported. The purpose of this investigation was to compare the complication and reintervention rates between the WS and Venovo stent (VS; BD, Franklin Lakes, NJ). METHODS: A random sample of 100 WS and 100 VS cases performed from April 2018 through December 2020 were selected for retrospective analysis. The demographics, presenting symptoms, and CEAP (Clinical, Etiology, Anatomy, Pathophysiology) class were assessed. The complication logs and 90-day follow-up data were reviewed for every case to assess the incidence of postoperative deep vein thrombosis, stent thrombosis, in-stent restenosis, bleeding, and transient back pain. RESULTS: WSs had been placed more often in the left common iliac vein segment (52 vs 1), and VSs had been placed more often in the left common iliac vein and external iliac vein segments (36 vs 63; P = .0069). The average diameter and length of the WSs and VSs were 19.7 ± 2.2 mm vs 15 ± 1.4 mm (P = 2.4∗10-44) and 80.8 ± 9 mm vs 117.6 ± 20.4 mm (P = 2.4∗10-38), respectively. The average number of stents per patient was 1.05 for the WSs and 1.03 for the VSs (P = .47). The reintervention rates were similar between the two groups: WS, n = 5; and VS, n = 4 (P = .74). Four of the five WS reinterventions were stent extensions to treat in-stent restenosis and recurrence of symptoms, and one was secondary to occlusion requiring ipsilateral venoplasty and stenting. Two of the four VS reinterventions were venoplasty for in-stent restenosis and two were stent extensions for symptom recurrence. Transient back pain was the most common complication (WS, 37%; VS, 47%; P = 0.28). Insertion site deep vein thrombosis had developed in the three patients in the WS group and four patients in the VS group (P = .71). No patient had experienced bleeding requiring hospitalization, and no stent fractures, stent migration, or deaths had occurred. CONCLUSIONS: The complication and reintervention rates between the WS and VS groups were similar. Both stents demonstrated evidence of in-stent stenosis requiring reintervention. Implanted VSs tended to be smaller in diameter and longer in length and covered the common and external iliac veins more often compared with the WSs. Therefore, one VS can be used to cover two territories compared with the WS for which two stents will be required to cover the same vein territory length.

Autoantibodies - enemies, and/or potential allies?

Autoantibodies are well known as potentially highly harmful antibodies which attack the host via binding to self-antigens, thus causing severe associated diseases and symptoms (e.g. autoimmune diseases). However, detection of autoantibodies to a range of disease-associated antigens has enabled their successful usage as important tools in disease diagnosis, prognosis and treatment. There are several advantages of using such autoantibodies. These include the capacity to measure their presence very early in disease development, their stability, which is often much better than their related antigen, and the capacity to use an array of such autoantibodies for enhanced diagnostics and to better predict prognosis. They may also possess capacity for utilization in therapy, in vivo. In this review both the positive and negative aspects of autoantibodies are critically assessed, including their role in autoimmune diseases, cancers and the global pandemic caused by COVID-19. Important issues related to their detection are also highlighted.

Evaluating immunogenicity of pathogen-derived T-cell epitopes to design a peptide-based smallpox vaccine.

Despite the eradication in 1980, developing safe and effective smallpox vaccines remains an active area of research due to the recent outbreaks and the public health concern that smallpox viruses could be used as bioterrorism weapons. Identifying immunogenic peptides (epitopes) would create a foundation for the development of a robust peptide-based vaccine. We previously identified a library of naturally-processed, human leukocyte antigen class I-presented vaccinia-derived peptides from infected B cells. In the current study, we evaluated the immunogenicity of these T-cell peptides in both transgenic mouse models and human peripheral blood mononuclear cells. A vaccine based on four selected peptides provided 100% protection against a lethal viral challenge. In addition, responses from memory T cells remained unchanged up to five months. Our results validate a practical approach for identifying and verifying immunogenic peptides for vaccine development and highlight the potential of peptide-based vaccines for various infectious diseases.

Identification of Src as a Therapeutic Target in Oesophageal Adenocarcinoma through Functional Genomic and High-Throughput Drug Screening Approaches.

Drug resistance limits the effectiveness of oesophageal adenocarcinoma (OAC) chemotherapies, leading to a poor prognosis for this disease. Elucidation of the underlying resistance mechanisms is key to enabling the identification of more effective treatments. This study, therefore, aims to identify novel therapeutic and/or chemotherapy sensitising drug targets in OAC. Transcriptional data from a cohort of 273 pre-treatment OAC biopsies, from patients who received neoadjuvant chemotherapy followed by surgical resection, were analysed using gene set enrichment analysis (GSEA) to determine differential gene expression between responding and non-responding OAC tumours. From this, 80 genes were selected for high-throughput siRNA screening in OAC cell lines with or without standard chemotherapy treatment. In parallel, cell viability assays were performed using a panel of FDA-approved drugs and combination index (CI) values were calculated to evaluate drug synergy with standard chemotherapy. Mechanisms of synergy were investigated using western blot, propidium iodide flow cytometry, and proliferation assays. Taken together, the screens identified that targeting Src, using either siRNA or the small molecule inhibitor dasatinib, enhanced the efficacy of chemotherapy in OAC cells. Further in vitro functional analysis confirmed Src inhibition to be synergistic with standard OAC chemotherapies, 5-fluorouracil (5-FU), and cisplatin (CDDP). In conclusion, a compound screen together with a functional genomic approach identified Src as a potential chemosensitising target in OAC, which could be assessed in a clinical study for poor prognosis OAC patients.

The Relationship Between Prior Cancer Diagnosis and All-Cause Dementia Progression Among US Adults.

BACKGROUND: Cancer-related cognitive impairment (CRCI), a frequent effect of cancer and its treatments, shares common cognitive symptoms with dementia syndromes. Cross-sectional studies demonstrate an inverse relationship between cancer and dementia. However, the longitudinal relationship between dementia decline and cancer has not been investigated. OBJECTIVE: To evaluate the association between cancer and longitudinal progression of dementia. METHODS: We extracted electronic health record data from July 2003 to February 2020 from a single academic medical center. We identified dementia and cancer history prior to dementia using ICD-9/10 codes. We measured cognitive decline with the Alabama Brief Cognitive Screener (ABCs). We used adjusted linear mixed models to estimate baseline cognition and rate of progression by cancer history, including differences by race. RESULTS: The study included 3,809 participants with dementia, of which 672 (17.6%) had cancer history. Those with cancer history had higher baseline cognition (ß: 1.07, 95% CI: 0.45, 1.69), but similar rate of decline. Non-Hispanic Blacks had lower cognitive scores at baseline and throughout follow-up regardless of cancer status compared to non-Hispanic Whites and other races/ethnicities with and without cancer history. CONCLUSION: In this longitudinal retrospective study, participants with cancer history demonstrate better cognition at dementia diagnosis and no difference in cognitive decline than those without cancer history. Smoking and comorbidities attenuate this association and results indicate non-Hispanic Blacks have worse cognitive outcomes in dementia regardless of cancer history than other race/ethnicity groups. Further exploration of the role of smoking, comorbidities, and race/ethnicity on cancer and dementia-related cognitive decline is needed.

Multiomic Characterization of High-Grade Serous Ovarian Carcinoma Enables High-Resolution Patient Stratification.

PURPOSE: High-grade serous ovarian carcinoma (HGSOC) is the most common ovarian cancer type; most patients experience disease recurrence that accumulates chemoresistance, leading to treatment failure. Genomic and transcriptomic features have been associated with differential outcome and treatment response. However, the relationship between events at the gene sequence, copy number, and gene-expression levels remains poorly defined. EXPERIMENTAL DESIGN: We perform multiomic characterization of a large HGSOC cohort (n = 362) with detailed clinical annotation to interrogate the relationship between patient subgroups defined by specific molecular events. RESULTS: BRCA2-mutant (BRCA2m) and EMSY-overexpressing cases demonstrated prolonged survival [multivariable hazard ratios (HR) 0.40 and 0.51] and significantly higher first- and second-line chemotherapy response rate. CCNE1-gained (CCNE1g) cases demonstrated underrepresentation of FIGO stage IV cases, with shorter survival but no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and Tothill-derived subtypes. IMR/C2 cases displayed higher BRCA1/2m frequency (25.5%, 32.5%) and significantly greater immune cell infiltration, whereas PRO/C5 cases had the highest CCNE1g rate (23.9%, 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair (HRR) genes was apparent across all transcriptomic subtypes (HR range, 0.48-0.68). There was significant co-occurrence of RB loss and HRR gene aberrations; RB loss was further associated with favorable survival within HRR-aberrant cases (multivariable HR, 0.50). CONCLUSIONS: These data paint a high-resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes.