Advanced medullary thyroid carcinoma uncovered by persistently elevated procalcitonin in a patient with COVID-19.

Summary: We report the case of an 88-year-old man hospitalized for COVID-19 with persistently very high procalcitonin (proCt) levels despite infection resolution. Since proCt is an adjunct tumor marker in the diagnosis of medullary thyroid carcinoma (MTC), serum calcitonin (Ct) was also measured showing very high levels. Computed tomography (CT) scan showed the presence of a thyroid mass and neck ultrasound revealed a solid isoechoic, inhomogeneous, 50 mm nodule in the right thyroid lobe, extended into the mediastinum. Fine needle aspiration (FNA) of the thyroid nodule confirmed the diagnosis of MTC. An 18F-fluorodopa positron emission tomography/computed tomography (PET/CT) scan revealed the presence of distant metastases in ribs, vertebrae, in the right iliac wing and the liver. Since surgery was not feasible, the patient was started on cabozantinib 40 mg/dL. After 16 months the patient is still on cabozantinib at the same dose, he reports complete autonomy in daily life activities, and serum Ct is still elevated; however, the imaging evaluation does not show signs of disease progression. Learning points: High procalcitonin serum values despite the absence of infection are suggestive of MTC. Advanced MTC with multiple metastases can have an indolent course and can go unrecognized for years. Cabozantinib is a valuable option for the treatment of advanced MTC.

Promising Role of Alkaloids in the Prevention and Treatment of Thyroid Cancer and Autoimmune Thyroid Disease: A Comprehensive Review of the Current Evidence.

Thyroid cancer (TC) and thyroid autoimmune disorders (AITD) are among the most common diseases in the general population, with higher incidence in women. Chronic inflammation and autoimmunity play a pivotal role in carcinogenesis. Some studies, indeed, have pointed out the presence of AITD as a risk factor for TC, although this issue remains controversial. Prevention of autoimmune disease and cancer is the ultimate goal for clinicians and scientists, but it is not always feasible. Thus, new treatments, that overcome the current barriers to prevention and treatment of TC and AITD are needed. Alkaloids are secondary plant metabolites endowed with several biological activities including anticancer and immunomodulatory properties. In this perspective, alkaloids may represent a promising source of prophylactic and therapeutic agents for TC and AITD. This review encompasses the current published literature on alkaloids effects on TC and AITD, with a specific focus on the pathways involved in TC and AITD development and progression.

Flexibility and Strength Effects of Adapted Nordic Walking and Myofascial Exercises Practice in Breast Cancer Survivors and Analysis of Differences.

Breast cancer treatments can elicit negative kinesiological side effects concerning both the posture and functional status of breast cancer survivors. As our body is functionally organized in myofascial meridians, physical exercise practice should favor a whole-body approach rather than a local one. The aim of the study was to investigate and compare the effects of two whole-body disciplines, i.e., adapted Nordic Walking and myofascial exercise, on the flexibility and strength performances in BCS. One hundred and sixty breast cancer survivors were trained three times per week for 12 weeks through adapted Nordic Walking or myofascial exercise. Handgrip, sit and reach, back scratch, and single leg back bridge tests and body composition were assessed at the beginning and completion of the training period. Linear mixed models showed no significant changes in body composition, whereas flexibility (p < 0.001), strength (p < 0.001), and muscle quality index (p = 0.003) changed independently from the treatment. When data modification has been analyzed according to sub-sample membership, no significant differences have been observed. Age, radiation therapy, and chemotherapy seem to have independent effects on several investigated variables. Twelve weeks of adapted myofascial exercise and Nordic Walking led to significant changes in flexibility, strength, and muscle quality in breast cancer survivors, with no apparent superiority of one approach over the other.

The Effects of Combined Exposure to Bisphenols and Perfluoroalkyls on Human Perinatal Stem Cells and the Potential Implications for Health Outcomes.

The present study investigates the impact of two endocrine disruptors, namely Bisphenols (BPs) and Perfluoroalkyls (PFs), on human stem cells. These chemicals leach from plastic, and when ingested through contaminated food and water, they interfere with endogenous hormone signaling, causing various diseases. While the ability of BPs and PFs to cross the placental barrier and accumulate in fetal serum has been documented, the exact consequences for human development require further elucidation. The present research work explored the effects of combined exposure to BPs (BPA or BPS) and PFs (PFOS and PFOA) on human placenta (fetal membrane mesenchymal stromal cells, hFM-MSCs) and amniotic fluid (hAFSCs)-derived stem cells. The effects of the xenobiotics were assessed by analyzing cell proliferation, mitochondrial functionality, and the expression of genes involved in pluripotency and epigenetic regulation, which are crucial for early human development. Our findings demonstrate that antenatal exposure to BPs and/or PFs may alter the biological characteristics of perinatal stem cells and fetal epigenome, with potential implications for health outcomes at birth and in adulthood. Further research is necessary to comprehend the full extent of these effects and their long-term consequences.

Cardiometabolic Profile, Physical Activity, and Quality of Life in Breast Cancer Survivors after Different Physical Exercise Protocols: A 34-Month Follow-Up Study.

BACKGROUND: Breast cancer (BC) and cardiovascular (CV) disease share many risk factors associated with worse outcomes, in terms of cancer relapse, CV events, and quality of life (QoL), that could be counteracted by physical exercise (PE). We aimed to assess the impact of a 12-week differential PE protocol on cardiometabolic profile, QoL, CV- and BC-related long-term outcomes, and physical activity (PA) in a cohort of BC survivors (BCS) not treated with chemotherapy. METHODS: 57 BCS participated in a 12-week PE protocol [aerobic exercise training (AET) or resistance exercise training (RET)]. Anthropometric and CV evaluation, health-related (HR)-QoL, daily PA, cortisol, and dehydroepiandrosterone sulfate (DHEA-S) levels were assessed before (T0) and after (T1) PE. We assessed BC and CV outcomes, HR-QoL, CV-QoL, and PA at the follow-up. RESULTS: RET improved waist circumference, DHEA-S, cortisol/DHEA-S, systolic and mean blood pressure, and ventricular/arterial coupling; AET ameliorated sagittal abdomen diameter and pulse wave velocity. Regarding HR-QoL, physical function improved only in AET group. At a mean 34 ± 3.6-month follow-up, we documented no significant differences in CV-QoL, HR-QoL, and PA or CV and BC outcomes. CONCLUSIONS: AET and RET determine specific, positive adaptations on many parameters strongly related to CV risk, CV and BC outcomes, and QoL, and should be included in any cardio-oncology rehabilitation program.

Impact of Maternal Lifestyle and Dietary Habits during Pregnancy on Newborn Metabolic Profile.

Expanded newborn screening (NBS) is a preventive program that allows for the early identification of over 40 congenital endocrine-metabolic diseases by analyzing dried blood spot samples collected from the newborn's heel within 48-72 h of birth. The determination of amino acids and acyl-carnitines by Flow Injection Analysis Tandem Mass Spectrometry (FIA-MS/MS) may also highlight metabolic alterations resulting from external factors, such as maternal nutrition. In the present study, we developed a questionnaire to investigate the eating habits of 109 women during pregnancy and statistically correlated the results from the investigation on dietary habits with the data obtained by the NBS laboratory of Abruzzo region (Italy). Parameters such as smoking, physical activity, and the intake of iodized salt, drugs, and supplements were analyzed. This study aimed to highlight how maternal lifestyle, diet, and drug intake during pregnancy may affect the neonatal metabolic profile, possibly generating false positive or false negative results in the NBS test. The results pointed out how the knowledge of maternal nutrition and lifestyle may also be precious in preventing misinterpretations of the neonatal metabolic profile, thereby reducing unnecessary stress for newborns and their parents and limiting costs for the health system.

Serum TSH and Daily Physical Activity in a Cohort of Nonagenarians: Results from the Mugello Study.

BACKGROUND: The current literature does not furnish clear data concerning the relationship between thyroid function, sedentary time and daily physical activity (PA) in older adults with euthyroid condition. The aim of this study was to investigate the association of serum Thyrotropin-Stimulating Hormone (TSH), free Triiodothyronine (fT3) and free Thyroxine (fT4) with sedentary time and PA in a cohort of nonagenarians. METHODS: A total of 108 nonagenarians (92.8 ± 3.2 years), participating in the Mugello Study, and with complete data on thyroid function, sedentary time, PA and sleeping (objectively collected through a multisensory device), were considered for the analysis. RESULTS: Mainly, TSH negatively correlated with time spent lying down, and positively correlated with METs. fT4 levels were negatively associated with mean daily metabolic equivalents (METs) and with low-intensity PA practice (LIPAT), and positively associated with lying down and sleeping time. Similar results have been shown in the female sample. Mainly, participants with high-normal (third tertile) versus low-normal TSH (first tertile) had higher moderate-intensity PA (MIPAT) (p = 0.03). In the female sample, first TSH tertile had higher METs (p = 0.010), LIPAT (p = 0.02), MIPAT (p = 0.01) and lower time lying down (p = 0.04) than third TSH tertile. CONCLUSION: High-normal serum TSH and low-normal fT4 are associated with higher levels and intensity of daily PA, together with higher MIPAT continuity, in the oldest-old.

Expanded Newborn Screening in Italy Using Tandem Mass Spectrometry: Two Years of National Experience.

Newborn screening (NBS) for inborn errors of metabolism is one of the most advanced tools for secondary prevention in medicine, as it allows early diagnosis and prompt treatment initiation. The expanded newborn screening was introduced in Italy between 2016 and 2017 (Law 167/2016; DM 13 October 2016; DPCM 12-1-2017). A total of 1,586,578 infants born in Italy were screened between January 2017 and December 2020. For this survey, we collected data from 15 Italian screening laboratories, focusing on the metabolic disorders identified by tandem mass spectrometry (MS/MS) based analysis between January 2019 and December 2020. Aminoacidemias were the most common inborn errors in Italy, and an equal percentage was observed in detecting organic acidemias and mitochondrial fatty acids beta-oxidation defects. Second-tier tests are widely used in most laboratories to reduce false positives. For example, second-tier tests for methylmalonic acid and homocysteine considerably improved the screening of CblC without increasing unnecessary recalls. Finally, the newborn screening allowed us to identify conditions that are mainly secondary to a maternal deficiency. We describe the goals reached since the introduction of the screening in Italy by exchanging knowledge and experiences among the laboratories.

High Incidence of Partial Biotinidase Deficiency in the First 3 Years of a Regional Newborn Screening Program in Italy.

Biotinidase deficiency (BD) is an autosomal recessive inherited disorder in which the enzyme biotinidase is totally or partially defective and the vitamin biotin is not recycled. BD meets the major criteria for a population screening program. Newborn bloodspot screening (NBS) allows early diagnosis of BD, thus preventing the high morbidity and mortality associated with untreated disease. Both profound and partial BD variant can be detected by NBS test, and serum enzyme activity and/or mutational analysis are required for definitive diagnosis. In Italy, BD is included in the screening panel for inborn errors of metabolism (IEMs) that has been declared mandatory in 2016. We analyzed the data of the first 3 years of the NBS for BD in our region (Abruzzo, Italy), with the aim to describe the outcomes of this recently introduced screening program. In over 26,393 newborns screened, we found 2 carriers and 16 cases with genotype associated with partial BD. Since the serum biotinidase assay has been recently introduced in our algorithm, only three of our newborns met the criteria of genetic and biochemical confirmation, with an incidence of 1:8797, which is in the high range of what has been reported in the literature. All affected infants carried the 1330G>C (D444H) variant in compound heterozygosis, with variants known to be associated with profound BD. A variant previously not described and likely pathogenic was found in one newborn. None of the infants had signs or symptoms. The study of the distribution of the enzyme activity in our population allowed us to validate the adopted cutoff with which the program has a positive predictive value of 18% and to analyze some preanalytical factors influencing biotinidase activity: A correlation of the enzyme activity with gestational age and time at specimen collection was found. Lower mean values of enzyme activity were found in infants born in the summer.

Thyroid Autoimmunity in Female Infertility and Assisted Reproductive Technology Outcome.

The regulation of the female reproductive system is one of the most relevant actions of thyroid hormones. Adequate thyroid hormones production is essential for normal menstrual function and fertility as well as for the successful maintenance of pregnancy. The relationship between reproductive failure and thyroid disorders is particularly relevant and attracts attention worldwide. Thyroid autoimmunity (TAI), defined by the presence of circulating antithyroid antibodies targeting thyroid peroxidase (TPOAb) and thyroglobulin (TgAb), is prevalent among women of reproductive age and is the most frequent cause of thyroid dysfunction. Several studies addressed the association between TAI, thyroid function, and fertility as well as pregnancy outcome after spontaneous or assisted conception. Infertility, miscarriages, and fetal-maternal complications are described in overt autoimmune hypothyroidism. More debatable is the role of mild thyroid dysfunction, mainly subclinical hypothyroidism (SCH), and TAI in the absence of thyroid dysfunction in infertility and reproductive outcome. Assisted reproductive technology (ART) has become an integral element of care for infertility. Women with TAI undergoing ART are of particular interest since they carry a higher risk of developing hypothyroidism after the ovarian stimulation but whether TAI, in absence of thyroid dysfunction, adversely affects ART outcome is still controversial. Likewise, the role of levothyroxine (LT4) in improving fertility and the success of ART in euthyroid women with TAI is unclear. This review discusses the role of TAI, in the absence of thyroid dysfunction, in infertility and in ART outcome.

Validation of the GSP®/DELFIA® Anti-SARS-CoV-2 IgG Kit Using Dried Blood Samples for High-Throughput Serosurveillance and Standardized Quantitative Measurement of Anti-Spike S1 IgG Antibody Responses Post-Vaccination.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a major global public health crisis. In response, researchers and pharmaceutical companies worked together for the rapid development of vaccines to reduce the morbidity and mortality associated with viral infection. Monitoring host immunity following virus infection and/or vaccination is essential to guide vaccination intervention policy. Humoral immune response to vaccination can be assessed with serologic testing, and indeed, many serological immunoassays are now in use. However, these many different assays make the standardization of test results difficult. Moreover, most published serological tests require venous blood sampling, which makes testing large numbers of people complex and costly. Here, we validate the GSP®/DELFIA® Anti-SARS-CoV-2 IgG kit using dried blood samples for high-throughput serosurveillance using standard quantitative measurements of anti-spike S1 IgG antibody concentrations. We then apply our validated assay to compare post-vaccination anti-SARS-CoV-2 S1 IgG levels from subjects who received a double dose of the AZD1222 vaccine with those vaccinated with a heterologous strategy, demonstrating how this assay is suitable for large-scale screening to achieve a clearer population immune picture.

Relationships between daily physical activity combinations and psychophysical health status of Italian breast cancer survivors.

In breast cancer survivors (BCS), the contemporaneous increase of sedentary time and reduction of physical activity (PA) requires early attention because it has negative consequences for their health. Aims of the study were to investigate: a) the correlations between PA, sedentarism, and health-related measures; b) the association between different patterns of daily activity and health-related outcomes. Two hundred and nineteen BCS (50.98 ± 6.28) were selected for this study. Psychological, anthropometric, endocrine, sleeping, and both daily sedentary time and PA variables were considered. Sedentarism and PA have opposite correlations with anthropometric variables, anxiety, depression, morning salivary cortisol, and sleeping characteristics. The first favors pathological values and the latter favors normal values. Regression tree analysis showed the impact of different daily sedentary time and PA combinations on the investigated variables and allowed the individualization of their optimal combination for health. Our results could be useful to healthcare providers and BCS.

Hormonal Regulation of the MHC Class I Gene in Thyroid Cells: Role of the Promoter "Tissue-Specific" Region.

In previous studies we have demonstrated that the expression of the Major Histocompatibility Complex (MHC) class I gene in thyrocytes is controlled by several hormones, growth factors, and drugs. These substances mainly act on two regions of the MHC class I promoter a "tissue-specific" region (-800 to -676 bp) and a "hormone/cytokines-sensitive" region (-500 to -68 bp). In a previous study, we have shown that the role of the "tissue-specific" region in the MHC class I gene expression is dominant compared to that of the "hormone/cytokines-sensitive" region. In the present report we further investigate the dominant role of the "tissue-specific" region evaluating the effect of thyroid stimulating hormone (TSH), methimazole (MMI), phenylmethimazole (C10), glucose and thymosin-α1. By performing experiments of electrophoretic mobility shift assays (EMSAs) we show that TSH, MMI and C10, which inhibit MHC class I expression, act on the "tissue-specific" region increasing the formation of a silencer complex. Glucose and thymosin-α1, which stimulate MHC class I expression, act decreasing the formation of this complex. We further show that the silencer complex is formed by two distinct members of the transcription factors families activator protein-1 (AP-1) and nuclear factor-kB (NF-kB), c-jun and p65, respectively. These observations are important in order to understand the regulation of MHC class I gene expression in thyroid cells and its involvement in the development of thyroid autoimmunity.

Resveratrol Enhances the Cytotoxic Activity of Lymphocytes from Menopausal Women.

Nutraceuticals and functional foods are the main sources of antioxidants and have positive effects on health through regulation of the redox balance. Accordingly, they represent a useful nutritional source for the prevention of noncommunicable diseases (NCDs). Menopausal women have an increased risk of developing NCDs due to hormonal dysregulation and the ongoing aging process. Accordingly, a healthy lifestyle and good nutritional habits are of utmost importance in this population. Resveratrol (RSV) is a natural polyphenol, and it is used as a nutraceutical given its estrogenic, anti-inflammatory, and antioxidant properties. The aim of this study was to analyze the effects of RSV on the lymphocyte cytotoxicity in menopausal women. Lymphocytes from 13 healthy menopausal women (56.18 ± 4.24 years) were isolated, and then cocultured with hTERT-HME1, a breast cell line with a precancerous phenotype. The results showed that, when treated with RSV, lymphocytes significantly increased the TNF-α production (p < 0.001), the formation of immune synapses (p = 0.009), and the target cell lysis (p = 0.002). No effects were detected in the lymphocyte total antioxidant capacity. In conclusion, RSV might enhance the immune surveillance in menopausal women by increasing the cytotoxic activity of lymphocytes.

Passive Immunity to SARS-CoV-2 at Birth Induced by Vaccination in the First Trimester of Pregnancy.

As is well known, the COVID-19 infection is affecting the whole world, causing a serious health, social and economic crisis. The viral infection can cause a mild or severe illness, depending on how effectively the virus is countered by the immune system. In this context, the position of pregnant women remains rather unknown. The case described here reports the immune response in a woman in good health and in her newborn son, having undergone complete vaccination during the first trimester of her pregnancy. We performed a serological assay, measuring IgG antibodies to SARS-CoV-2, by a fully automated solid phase DELFIA (time-resolved fluorescence) immunoassay in a few drops of blood, collected by a finger-prick and spotted on filter paper. The dried blood spot (DBS) sample we used is the same type of sample routinely used in a newborn screening program test. Such a simple and minimally invasive approach allowed us to monitor both the mother and the newborn soon after birth for their anti-SARS-CoV-2 IgG levels. The serological test on the DBS carried out on both mother and newborn revealed the presence of anti-SARS-CoV-2 IgG antibodies up to 7 months after vaccination in the mother, and already at 48 h of life in the newborn.

Non-Conventional Clinical Uses of TSH Receptor Antibodies: The Case of Chronic Autoimmune Thyroiditis.

Anti TSH receptor antibodies (TSHrAb) are a family of antibodies with different activity, some of them stimulating thyroid function (TSAb), others with blocking properties (TBAb), it is a common finding that antibodies with different function might coexist in the same patient and can modulate the function of the thyroid. However, most of the labs routinely detect all antibodies binding to the TSH receptor (TRAb, i.e. TSH-receptor antibodies detected by binding assay without definition of functional property). Classical use of TSHr-Ab assay is in Graves' disease where they are tested for diagnostic and prognostic issues; however, they can be used in specific settings of chronic autoimmune thyroiditis (CAT) as well. Aim of the present paper is to highlight these conditions where detection of TSHr-Ab can be of clinical relevance. Prevalence of TSHrAb is different in in the 2 main form of CAT, i.e. classical Hashimoto's thyroiditis and in atrophic thyroiditis, where TBAb play a major role. Simultaneous presence of both TSAb and TBAb in the serum of the same patient might have clinical implication and cause the shift from hyperthyroidism to hypothyroidism and vice versa. Evaluation of TRAb is recommended in case of patients with Thyroid Associated Orbitopathy not associated with hyperthyroidism. At present, however, the most relevant recommendation for the use of TRAb assay is in patients with CAT secondary to a known agent; in particular, after treatment with alemtuzumab for multiple sclerosis. In conclusion, the routine use of anti-TSH receptor antibodies (either TRAb or TSAb/TBAb) assay cannot be suggested at the present for diagnosis/follow up of patients affected by CAT; there are, however, several conditions where their detection can be clinically relevant.

BNT162b2 mRNA Vaccination Leads to Long-Term Protection from COVID-19 Disease.

The efficacy of SARS-CoV-2 mRNA-based vaccines in preventing COVID-19 disease has been extensively demonstrated; however, it is of uttermost importance to acquire knowledge on the persistence of immune-protection both in terms of levels of neutralizing antibodies and specialized memory cells. This can provide important scientific basis for decisions on the need of additional vaccine doses and on when these should be administered thus resulting in an improvement in vaccination schedules. Here, we briefly report the changes in antibody levels and cellular immunity following BNT162b2 administration. We show an important fall in anti S1-Spike antibodies in BNT162b2 vaccinated subjects overtime, paralleled by a contextual consolidation of specific spike (S) T-cells, mainly of the CD8+ compartment. Contrariwise, CD4+ S-specific response shows a considerable interindividual variability. These data suggest that the well-known antibody drop in vaccinated subjects is replaced by memory cell consolidation that can protect from severe adverse effects of SARS-CoV-2 infection.

Picture of the Favourable Immune Profile Induced by Anti-SARS-CoV-2 Vaccination.

COVID-19 pandemic has hit people's health, economy, and society worldwide. Great confidence in returning to normality has been placed in the vaccination campaign. The knowledge of individual immune profiles and the time required to achieve immunological protection is crucial to choose the best vaccination strategy. We compared anti-S1 antibody levels produced over time by BNT162b2 and AZD1222 vaccines and evaluated the induction of antigen-specific T-cells. A total of 2569 anti-SARS-CoV-2 IgG determination on dried blood spot samples were carried out, firstly in a cohort of 1181 individuals at random time-points, and subsequently, in an independent cohort of 88 vaccinated subjects, up to the seventeenth week from the first dose administration. Spike-specific T-cells were analysed in seronegative subjects between the two doses. AZD1222 induced lower anti-S1 IgG levels as compared to BNT162b2. Moreover, 40% of AZD1222 vaccinated subjects and 3% of BNT162b2 individuals resulted in seronegative during all the time-points, between the two doses. All these subjects developed antigen-specific T cells, already after the first dose. These results suggest that this test represents an excellent tool for a wide sero-surveillance. Both vaccines induce a favourable immune profile guaranteeing efficacy against severe adverse effects of SARS-CoV-2 infection, already after the first dose administration.

Partial Biotinidase Deficiency Revealed Imbalances in Acylcarnitines Profile at Tandem Mass Spectrometry Newborn Screening.

Biotinidase (BTD) deficiency is an autosomal recessive inherited neurocutaneous disorder. BTD recycles the vitamin biotin, a coenzyme essential for the function of four biotin-dependent carboxylases, including propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase. Due to deficient activities of the carboxylases, BTD deficiency is also recognized as late-onset multiple carboxylase deficiency and is associated with secondary alterations in the metabolism of amino acids, carbohydrates, and fatty acids. BTD deficiency can be classified as "profound", with less than 10% of mean normal activity, and as "partial" with 10-30% of mean normal activity. Newborn screening (NBS) of BTD deficiency is performed in most countries and is able to detect both variants. Moreover, mild metabolic alterations related to carboxylase deficiency in profound BTD deficiency could result and possibly be revealed in the metabolic profile by tandem mass spectrometry (MS/MS) NBS. Here, we report the case of a newborn female infant with an initial suspected BTD deficiency at the NBS test, finally confirmed as a partial variant by molecular testing. Although BTD deficiency was partial, interestingly her metabolic profile at birth and during the follow-up tests revealed, for the first time, alterations in specific acylcarnitines as a possible result of the deficient activity of biotin-dependent carboxylases.