An enhancer variant associated with breast cancer susceptibility in Black women regulates TNFSF10 expression and antitumor immunity in triple-negative breast cancer.

Women of African ancestry have the highest mortality from triple-negative breast cancer (TNBC) of all racial groups. To understand the genomic basis of breast cancer in the populations, we previously conducted genome-wide association studies and identified single nucleotide polymorphisms (SNPs) associated with breast cancer in Black women. In this study, we investigated the functional significance of the top associated SNP rs13074711. We found the SNP served as an enhancer variant and regulated TNFSF10 (TRAIL) expression in TNBC cells, with a significant association between the SNP genotype and TNFSF10 expression in breast tumors. Mechanistically, rs13074711 modulated the binding activity of c-MYB at the motif and thereby controlled TNFSF10 expression. Interestingly, TNFSF10 expression in many cancers was consistently lower in African Americans compared with European Americans. Furthermore, TNFSF10 expression in TNBC was significantly correlated with the expression of antiviral immune genes and was regulated by type I interferons (IFNs). Accordingly, loss of TNFSF10 resulted in a profound decrease in apoptosis of TNBC cells in response to type I IFNs and poly(I:C), a synthetic analogue of double stranded virus. Lastly, in a syngeneic mouse model of breast cancer, TNFSF10-deficiency in breast tumors decreased tumor-infiltrated CD4+ and CD8+ T cell quantities. Collectively, our results suggested that TNFSF10 plays an important role in the regulation of antiviral immune responses in TNBC, and the expression is in part regulated by a genetic variant associated with breast cancer in Black women. Our results underscore the important contributions of genetic variants to immune defense mechanisms.

Using New Hampshire Colonoscopy Registry data to assess United States and European post-polypectomy surveillance guidelines.

BACKGROUND: Our goal was to compare the updated European Society of Gastrointestinal Endoscopy (ESGE) and United States Multi-Society Task Force on Colorectal Cancer (USMSTF) high risk groups in predicting metachronous advanced neoplasia on first follow-up colonoscopy and long-term colorectal cancer (CRC). METHODS: We compared advanced metachronous neoplasia risk (serrated polyps ≥ 1 cm or with dysplasia, advanced adenomas [≥ 1 cm, villous, high grade dysplasia], CRC) on first surveillance colonoscopy in patients with high risk findings according to ESGE versus USMSTF guidelines. We also compared the positive and negative predictive values (PPV, NPV) of both guidelines for metachronous neoplasia. RESULTS: The risk for metachronous neoplasia in our sample (n = 20 458) was higher in the high risk USMSTF (3 year) (13.6 %; 95 %CI 12.3-14.9) and ESGE groups (13.6 %; 95 %CI 12.3-15.0) compared with the lowest risk USMSTF (5.1 %; 95 %CI 4.7-5.5; P < 0.001) and ESGE categories (6.3 %; 95 %CI 6.0-6.7; P < 0.001), respectively. Adding other groups such as USMSTF 5-10-year and 3-5-year groups to the 3-year category resulted in minimal change in the PPV and NPV for metachronous advanced neoplasia. High risk ESGE (hazard ratio [HR] 3.03, 95 %CI 1.97-4.65) and USMSTF (HR 3.07, 95 %CI 2.03-4.66) designations were associated with similar long-term CRC risk (CRC per 100 000 person-years: USMSTF 3-year group 3.54, 95 %CI 2.68-4.68; ESGE high risk group: 3.43, 95 %CI 2.57-4.59). CONCLUSION: Performance characteristics for the ESGE and USMSTF recommendations are similar in predicting metachronous advanced neoplasia and long-term CRC. The addition of risk groups, such as the USMSTF 5-10-year and 3-5-year groups to the USMSTF 3-year category did not alter the PPV or NPV significantly.

Immunologic basis of vaccine vectors.

Efforts to make vaccines against infectious diseases as well as immunotherapies for cancer, autoimmune diseases and allergy have utilized a variety of heterologous expression systems, including viral and bacterial vectors, as well as DNA and RNA constructs. This review explores the immunologic rationale and provides an update of insights obtained from preclinical and clinical studies of such vaccines.

High-Frequency Distortion-Product Otoacoustic Emission Repeatability in a Patient Population.

OBJECTIVES: Distortion-product otoacoustic emissions (DPOAEs) are repeatable over time at lower frequencies (≤8 kHz) and higher frequencies (>8 kHz) in healthy, normal-hearing subjects. The purpose of this study was to examine the repeatability of DPOAEs measured with high-frequency (HF) stimuli in a patient population. It was hypothesized that HF DPOAEs would be repeatable over four trials. DESIGN: DPOAEs were measured in 40 cystic fibrosis (CF) patients (17 females and 23 males) with measurable behavioral thresholds and present DPOAEs for at least 2 of the high frequencies tested (8 to 16 kHz). A depth-compensated simulator sound pressure level (SPL) method of calibration was utilized. Each patient attended four trials, in which a complete set of data were collected. At each trial, three different DPOAE paradigms were completed. First, a discrete frequency sweep was measured between 8 and 16 kHz with a ratio (f2/f1) of 1.2 and levels of 65/50 dB SPL for L1/L2. Next, ratio and level sweeps were obtained at the two highest frequencies with a present DPOAE determined from the discrete frequency sweep, and the results were used to calculate DPOAE group delay and DPOAE detection thresholds, respectively. Ratio sweeps were collected with f2/f1 varied from 1.1 to 1.3 and stimulus levels of 60/45 dB SPL (L1/L2). Level sweeps were collected with an f2/f1 of 1.22 and L2 = 50 and L1 varied between 20 and 70 dB SPL. Differences and correlations between trials, SE of the measurement, and confidence intervals were calculated, as well as a repeated-measures analysis of variance. RESULTS: DPOAE response and behavioral threshold variability in CF patients were not significantly different across four trials. It can be expected in 95% of CF patients that differences between trials of DPOAE levels, group delay, and detection thresholds and behavioral thresholds are less than 6.26 dB, 0.87 msec, 9.34 dB, and 9.60 dB, respectively. CONCLUSIONS: HF DPOAEs were repeatable across four test trials for all three paradigms measured in a group of CF patients. These results are encouraging for the measurement of HF DPOAEs to be monitored in those exposed to ototoxic agents.

Expert opinion in the management of aqueous Deficient Dry Eye Disease (DED).

BACKGROUND: Dry eye disease (DED) affects millions of people worldwide. There are a variety of new treatments beyond traditional therapies such as preservative free artificial tears. Here, we conduct a survey to identify the most common treatments used among specialists and assess their interest in newer therapies. METHODS: An international survey was distributed to dry eye researchers and expert practitioners via an internet survey. The survey data collected were analyzed with descriptive statistics. RESULTS: One hundred and fifteen respondents completed the survey; of these, 66 % were cornea specialists. The most commonly prescribed topical treatments included cyclosporine A (CSA) 0.05 % (71/104, 68 %), fluorometholone (FML) 0.1 % (59/99, 60 %), loteprednol etabonate 0.5 % (50/99, 51 %), and autologous serum eye drops (ASD; 48/97, 49 %). The most commonly prescribed non-topical medications included essential fatty acid supplements (72/104, 69 %), low-dose doxycycline (oral; 61/100, 61 %), and flaxseed supplements (32/96, 33 %) as well as punctal plugs (76/102, 75 %). Respondents reported treatment with topical corticosteroids for 2 to 8 weeks (46/86, 53 %), followed by less than 2 weeks (24/86, 28 %) and with topical CSA between 2 to 8 weeks (45/85, 53 %) followed by 2 to 6 months (24/85, 28 %). The top three signs and symptoms reported to indicate treatment response were, in order, fluorescein staining of the cornea, reduction in foreign body sensation, and reduction in burning sensation. CONCLUSION: This survey offers insight into current expert opinion in the treatment of DED. The results of this survey are hypothesis generating and will aid in the design of future clinical studies.

Ethical issues for vaccines and immunization.

Vaccination is the only type of medical intervention that has eliminated a disease successfully. However, both in countries with high immunization rates and in countries that are too impoverished to protect their citizens, many dilemmas and controversies surround immunization. This article describes some of the ethical issues involved, and presents some challenges and concepts for the global community.

DNA vaccines: an historical perspective and view to the future.

This review provides a detailed look at the attributes and immunologic mechanisms of plasmid DNA vaccines and their utility as laboratory tools as well as potential human vaccines. The immunogenicity and efficacy of DNA vaccines in a variety of preclinical models is used to illustrate how they differ from traditional vaccines in novel ways due to the in situ antigen production and the ease with which they are constructed. The ability to make new DNA vaccines without needing to handle a virulent pathogen or to adapt the pathogen for manufacturing purposes demonstrates the potential value of this vaccine technology for use against emerging and epidemic pathogens. Similarly, personalized anti-tumor DNA vaccines can also readily be made from a biopsy. Because DNA vaccines bias the T-helper (Th) cell response to a Th1 phenotype, DNA vaccines are also under development for vaccines against allergy and autoimmune diseases. The licensure of four animal health products, including two prophylactic vaccines against infectious diseases, one immunotherapy for cancer, and one gene therapy delivery of a hormone for a food animal, provides evidence of the efficacy of DNA vaccines in multiple species including horses and pigs. The size of these target animals provides evidence that the somewhat disappointing immunogenicity of DNA vaccines in a number of human clinical trials is not due simply to the larger mass of humans compared with most laboratory animals. The insights gained from the mechanisms of protection in the animal vaccines, the advances in the delivery and expression technologies for increasing the potency of DNA vaccines, and encouragingly potent human immune responses in certain clinical trials, provide insights for future efforts to develop DNA vaccines into a broadly useful vaccine and immunotherapy platform with applications for human and animal health.

Downstaging Hepatocellular Carcinoma with Checkpoint Inhibitor Therapy Improves Access to Curative Liver Transplant.

PURPOSE: Liver transplantation is curative for hepatocellular carcinoma (HCC). Checkpoint inhibitor therapy (CPIT) has been used in unresectable HCC, but recent advances have demonstrated CPIT as an innovative method of downstaging advanced HCC with the caveat that CPIT prior to transplantation has risks including irreversible graft rejection. We report the outcomes of Mayo Clinic Arizona patients who underwent downstaging with CPIT. METHODS: This retrospective chart review was conducted for Mayo Clinic Arizona patients who were diagnosed with HCC who underwent downstaging with CPIT with the goal of meeting criteria for transplantation. RESULTS: We present nine cases with HCC outside Milan who underwent CPIT. Four received a transplant; one was delisted due to his exceptional therapeutic response. All received liver-directed therapy. Peak alpha-fetoprotein pre-CPIT ranged from 8-29,523 ng/mL, which decreased to 2.2-19.6 ng/mL on CPIT. CPIT included atezolizumab/bevacizumab, ipilimumab/nivolumab, nivolumab, and pembrolizumab; one patient received two regimens. CPIT was held prior to transplant at a median of 3 months. Three patients received methylprednisolone for immunosuppression induction; one received thymoglobulin. One patient developed acute cellular rejection at 5 weeks, 9 weeks, and 5 months post-transplant; given the late onset, these were not attributed to CPIT and were successfully treated. During an average follow-up of 16.5 months, no tumor recurrence has occurred. CONCLUSION: We describe nine patients with HCC outside Milan with inadequate response with liver-directed therapy, who achieved marked responses with CPIT, allowing for consideration of successful liver transplantation. Our case series supports the consideration of locoregional therapies and CPIT for downstaging to within transplant criteria.

Clinical presentation of Warburg effect in aggressive lymphoma: a case report.

BACKGROUND: The Warburg effect is a rare condition in tumor biology, illustrated by significant lactate production in the presence of oxygen. The Warburg effect is associated with very poor prognosis in patients with malignancy. CASE PRESENTATION: We report a 76-year-old Caucasian woman with double-expressor diffuse large B cell lymphoma who presented with severe lactic acidosis and extreme hypoglycemia with normal mentation. Her lactic acidosis was initially controlled with a bicarbonate infusion, and the patient was started promptly on steroids, followed by chemotherapy, but her clinical course was complicated by tumor lysis syndrome, acute renal failure requiring hemodialysis, and progressive liver failure. She manifested a temporary clinical response to chemotherapy but eventually died of complications. CONCLUSIONS: This case demonstrates the importance of prompt recognition of the Warburg effect, aggressive supportive measures, and early initiation of chemotherapy. Future studies are needed to characterize the role of hemodialysis in this setting.

Hypopyon uveitis following LASIK in a patient with ulcerative colitis.

PURPOSE: To present a case of unilateral hypopyon uveitis that began 15 days after uneventful bilateral LASIK in a 24-year-old man with an undisclosed history of ulcerative colitis. METHODS: Case report. RESULTS: The hypopyon uveitis completely resolved after treatment with aggressive topical and oral steroid agents in combination with topical antibiotic coverage. CONCLUSIONS: Although rare, visually significant hypopyon uveitis may arise after LASIK in the setting of ulcerative colitis and positive human leukocyte antigen (HLA) B27. Early recognition and treatment can result in an excellent outcome. The exact relationship between hypopyon uveitis and LASIK is impossible to ascertain.

Can successful vaccines teach us how to induce efficient protective immune responses?

Some recently introduced vaccines that have excellent efficacy records have been developed without a clear understanding of their mechanism of protection. In fact, successful vaccines have often emerged out of empirical observations and have only rarely been the result of a rational use of the continuously increasing immunological knowledge available to scientists. However, a posteriori deciphering of the biological bases for the efficacy of successful vaccines should be an essential component of research efforts directed at the development of new vaccines for the most challenging infectious diseases.

A comparative study of pulse rate variability and heart rate variability in healthy subjects.

Both heart rate variability (HRV) and pulse rate variability (PRV) are noninvasive means for the assessment of autonomic nervous control of the heart. However, it is not settled whether or not the PRV obtained from either hand can be the surrogate of HRV. The HRV measures obtained from electrocardiographic signals and the PRV measures obtained from the pulse waves recorded from the index fingers of both hands were compared in normal subjects by using linear regression analysis and Bland and Altman method. Highly significant correlations (P < 0.001, 0.89 < r < 1.0) were found between all HRV measures and the corresponding PRV measures of both hands. However, there were insufficient agreements in some measures between pairwise comparisons among HRV, right PRV and left PRV except heart rate and ultra-low frequency power (ULFP). The PRV of either hand is close to, but not the same as the HRV in healthy subjects. The HRV, right PRV and left PRV are not surrogates of one another in normal subjects except heart rate and ULFP. Since HRV is generally accepted as the standard method for the assessment of the autonomic nervous modulation of a subject, the PRV of either hand may not be suitable for the assessment of the cardiac autonomic nervous modulation of the subject.

DNA and mRNA Vaccines for Chronic Viral Infections and Cancer: Rationale, Mechanisms, and Progress.

Interest in the capabilities of nucleic acid vaccines, (DNA and mRNA vaccines) for both prophylactic and therapeutic uses have greatly increased following the successful deployment of two mRNA and, on a more limited scale, one DNA vaccine for COVID-19. In addition to targeting other pathogens for prophylactic vaccines, efforts are also being made towards using them for therapies for chronic infections and cancer. An examination of past and current successes for such therapies using other technologies with an emphasis on the immunological mechanisms will be provided followed by an assessment of the relevant characteristics of DNA and mRNA vaccines to predict their utility for therapies for chronic viral infections and cancer. Efforts and progress for these targets will be described.

Starch and sugars as determinants of postharvest shelf life and quality: some new and surprising roles.

Starch and sugars account for most of the dry weight of horticultural crops and in many species, are known determinants of quality. However, we posit that these carbohydrates often have less-obvious roles in plant tissues with direct implications for the postharvest quality and produce shelf life. The latter has not been given as much attention, but with the recent interest in reducing the scale of postharvest waste and loss, we highlight how dynamic changes in the spatial-temporal accumulation of carbohydrates, can influence myriads of biological processes affecting postharvest attributes. Versatile roles, some surprising, that carbohydrates play in determining produce of high value to consumers, are highlighted, and gene targets for biotechnological improvement are specified.

WHO informal consultation on regulatory considerations for evaluation of the quality, safety and efficacy of RNA-based prophylactic vaccines for infectious diseases, 20-22 April 2021.

This paper presents the key outcomes of the above WHO informal consultation with global stakeholders including regulatory authorities, vaccine developers and manufacturers, academia and other international health organizations and institutions involved in the development, evaluation and use of messenger RNA (mRNA) vaccines. The aim of the consultation was to further clarify the main principles to be presented in an upcoming WHO guidance document on the regulatory considerations in evaluating the quality, safety and efficacy of mRNA prophylactic vaccines for infectious diseases. This WHO guidance document is intended to facilitate global mRNA vaccine development and regulatory convergence in the assessment of such vaccines. The urgent need to develop such a document as a new WHO written standard is outlined in this report along with the key scientific and regulatory challenges. A number of key conclusions are provided at the end of this report along with an update on the steps taken following this meeting.

Power spectral analysis of plethysmographic pulse waveform in pregnant women.

OBJECTIVE: To investigate the effect of pregnancy on the pulse wave of the mother. PATIENTS AND METHODS: Pulse waveforms recorded via a pulse oximeter from the left index finger of non-pregnant women and pregnant women in the three trimesters of pregnancy were Fourier transformed into power spectra. Spectral indices of the power spectra of pulse waveform were obtained and compared among non-pregnant women and pregnant women in the three trimesters of pregnancy. RESULTS: The power of harmonics of pulse wave decayed exponentially with respect to the order of harmonics. The exponent and initial value of exponential decay for the power of harmonics and the power of the 2nd harmonic were increased, whereas the total power of pulse and the powers of higher order harmonics were decreased during pregnancy. CONCLUSION: The power of harmonics of pulse wave can be described by an exponential decay function with respect to the order of harmonics in both non-pregnant and pregnant women. The effects of pregnancy on the pulse wave are the reduction in the total power of pulse and the power of higher order harmonics, and the increase in the power of lower order harmonics in the power spectrum of pulse wave. This effect of pregnancy on the pulse wave might be caused by the decrease in vascular resistance during pregnancy, the increase in workload on the heart due to increased demand of the growing fetus, and the aortocaval compression caused by the progressively enlarged gravid uterus and fetus.

The Key Role of Nucleic Acid Vaccines for One Health.

The ongoing SARS-CoV-2 pandemic has highlighted both the importance of One Health, i.e., the interactions and transmission of pathogens between animals and humans, and the potential power of gene-based vaccines, specifically nucleic acid vaccines. This review will highlight key aspects of the development of plasmid DNA Nucleic Acid (NA) vaccines, which have been licensed for several veterinary uses, and tested for a number of human diseases, and will explain how an understanding of their immunological and real-world attributes are important for their efficacy, and how they helped pave the way for mRNA vaccines. The review highlights how combining efforts for vaccine development for both animals and humans is crucial for advancing new technologies and for combatting emerging diseases.

Development of mRNA Vaccines: Scientific and Regulatory Issues.

The global research and development of mRNA vaccines have been prodigious over the past decade, and the work in this field has been stimulated by the urgent need for rapid development of vaccines in response to an emergent disease such as the current COVID-19 pandemic. Nevertheless, there remain gaps in our understanding of the mechanism of action of mRNA vaccines, as well as their long-term performance in areas such as safety and efficacy. This paper reviews the technologies and processes used for developing mRNA prophylactic vaccines, the current status of vaccine development, and discusses the immune responses induced by mRNA vaccines. It also discusses important issues with regard to the evaluation of mRNA vaccines from regulatory perspectives. Setting global norms and standards for biologicals including vaccines to assure their quality, safety and efficacy has been a WHO mandate and a core function for more than 70 years. New initiatives are ongoing at WHO to arrive at a broad consensus to formulate international guidance on the manufacture and quality control, as well as nonclinical and clinical evaluation of mRNA vaccines, which is deemed necessary to facilitate international convergence of manufacturing and regulatory practices and provide support to National Regulatory Authorities in WHO member states.