International Journal of Translational Medicine

Type 1 Diabetes (T1D) is a chronic metabolic disorder for which current treatments are unable to prevent the onset of complications. Previously, we used an adeno-associated viral vector (AAV8) to deliver furin-cleavable human insulin (INS-FUR) to the livers of diabetic non-obese diabetic (NOD) mice to reverse T1D. The use of the traditional AAV8-INS-FUR vector could not bring about normoglycemia. However, this vector, coupled with a transposon system in the AAV8/piggyBac-INS-FUR vector, was able to do so. This study aimed to investigate the transcriptomic profiles of the livers of diabetic, AAV8-INS-FUR-transduced, and AAV8/piggyBac-INS-FUR-transduced NOD mice and compare these to the normal liver to identify genetic differences resulting from delivery of the AAV8/piggyBac-INS-FUR vector which produced normoglycemia. Differential gene expression was determined by RNA-Seq analysis and differentially expressed genes from each treatment were mapped onto cellular pathways to determine the treatments’ cell signaling and downstream effects. We observed distinct differences between the piggyBac-transduced and diabetic models, particularly in terms of metabolic function and the upregulation of key pancreatic markers in the liver of piggyBac-transduced animals. The success of the AAV8/piggyBac-INS-FUR vector in achieving normoglycemia through stable transduction was evident. However, further engineering is necessary to achieve complete pancreatic transdifferentiation of liver cells. Full article

Normal contractile function of the myocardium is essential for optimal cardiovascular health. Evaluating drug effects on cardiomyocyte function at the cellular level is difficult for long-term studies. Present culture systems rely on isolated, cardiomyocyte preparations or cardiomyocytes derived from pluripotent stem cells (PSCs), all of which have limitations. Isolated, endogenous cardiomyocytes do not remain contractile in culture long term. While PSC-derived cardiomyocytes show contractile activity for longer periods of time, their phenotype is more embryonic than adult. Here we report that dexamethasone (DEX) treatment of adult mouse atrial tissue can extend its functionality in culture. Normally, cardiac explants cease their capacity as a contractile tissue within the first month, as the tissue flattens and spreads out on the culture substrate, while the cells dedifferentiate and lose their myocardial phenotype. However, with DEX treatment, cardiac explants maintain their contractile function, 3D morphology, and myocyte phenotype for up to 6 months. Moreover, DEX also preserved the contractile phenotype of isolated rat cardiomyocytes. These data with DEX suggest that simple modifications in culture conditions can greatly improve the long-term utility of in vitro model systems for screening drugs and agents that could be employed to alleviate human cardiac disease. Full article

Preferentially expressed antigen in melanoma (PRAME) is a cancer testis antigen (CTA) that is selectively expressed in certain somatic tissues, predominantly in the testis, and is overexpressed in various cancers. PRAME family proteins are leucine-rich repeat proteins that are localized in the nucleus and cytoplasm, with multifaceted roles in immunity, during gametogenesis and in the overall reproduction process. It is a widely studied CTA and has been associated with the prognosis and therapeutic outcomes in patients with epithelial and non-epithelial tumors. PRAME has also been studied extensively as a therapeutic target. Moreover, it has been found to play a role in most of the well-known cancer hallmarks. Interestingly, the role of PRAME in tumorigenesis is paradoxical. Over the last decade, PRAME has garnered substantial interest as a target for immunotherapy. There are multiple clinical trials and pre-clinical studies targeting PRAME alone or in combination with other tumor antigens. This review article is an attempt to update our knowledge and understanding of the context-dependent oncogenic functions of PRAME in various carcinomas, and the current immunotherapeutic strategies, challenges, and perspectives on developing newer strategies to target PRAME for a better outcome. Full article

Endoscopic spine surgery (ESS) began more than 20 years ago as percutaneous endoscopic discectomy and has evolved to the present day. This technique offers many advantages, including a short hospital stay, minimal trauma and blood loss, the option of local or epidural anesthesia with sedation, a low rate of nosocomial infections, early recovery, and a quick return to work and daily activities. The success rate of this technique ranges from 83% to 90% in operated patients. This article aims to provide an overview of indications, versatility of the technique, advantages, contraindications and limitations, and also a reflection on the possible contraindications and limitations of the technique. Full article

Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is an important target of monoclonal antibody (mAb) therapy such as trastuzumab. Due to the development of trastuzumab–deruxtecan, an antibody-drug conjugate, the targetable HER2-positive breast cancer patients have been expanded. To evaluate the developing modalities using anti-HER2 mAbs, reliable preclinical mouse models are required. Therefore, sensitive mAbs against mouse HER2 (mHER2) should be established. This study developed anti-mHER2 mAbs using the Cell-Based Immunization and Screening (CBIS) method. The established anti-mHER2 mAbs, H₂Mab-300 (rat IgG_2b, kappa) and H₂Mab-304 (rat IgG₁, kappa), reacted with mHER2-overexpressed Chinese hamster ovary-K1 (CHO/mHER2) and endogenously mHER2-expressed cell line, NMuMG (a mouse mammary gland epithelial cell) via flow cytometry. Furthermore, these mAbs never recognized mHER2-knockout NMuMG cells. The kinetic analysis using flow cytometry indicated that the dissociation constant (K_D) values of H₂Mab-300 and H₂Mab-304 for CHO/mHER2 were 1.2 × 10⁻⁹ M and 1.7 × 10⁻⁹ M, respectively. The K_D values of H₂Mab-300 and H₂Mab-304 for NMuMG were 4.9 × 10⁻¹⁰ M and 9.0 × 10⁻¹⁰ M, respectively. These results indicated that H₂Mab-300 and H₂Mab-304 could apply to the detection of mHER2 using flow cytometry and may be useful to obtain the proof of concept in preclinical studies. Full article

In this study, the effects of foods containing lipopolysaccharide (LPS) from Pantoea agglomerans (LPSp) on immunity were preliminarily investigated using a double-blind, placebo-controlled, randomized, parallel-group comparative study design. Thirty healthy subjects aged ≥ 20 years (four males and twenty-six females; mean age 49 ± 9.2 years) were randomly assigned to the LPS-containing food group (488 μg/day; LPS) or placebo group. Each food was consumed for 8 weeks, and a subjective survey of cold symptoms (Wisconsin Upper Respiratory Symptom Questionnaire) and allergic symptoms of the eyes and nose were conducted. Phagocytic capacity and lymphocyte counts were measured as indicators of immune function. There were no significant between-group differences with respect to any of the investigated items. On sub-group analysis of eye–nose allergy symptom score, confined only to subjects who reported eye–nose allergic symptoms in previous years, the LPS group showed a trend toward milder symptoms compared to the placebo group. In addition, when the symptom scores were compared only for subjects who developed eye–nose allergies during the study period, the LPS group showed significantly lower overall scores and eye symptom scores compared to the placebo group. These results suggest that the consumption of LPS-containing foods may alleviate or prevent eye–nose allergies. There were no statistically predominant changes in hematology and blood biochemistry tests, indicating that continued consumption of LPS-containing foods is safe. (UMIN000046154). Full article

Androgen deprivation therapy (ADT) is the basis for the control of prostate cancer. High levels of prostate-specific antigen (PSA) and high Gleason grade correlate, define the aggressiveness of the cancer in order to establish its treatment and prognosis. This work evaluated the response of 910 patients diagnosed with prostate cancer, separated into three groups according to their response to treatment by ADT: (1) sensitive (TSPC); (2) palliative and did not accept treatment, and (3) group with recurrence or treatment resistance (TRPC). All patients with prostate cancer treated with ADT, and regardless of whether or not they had undergone surgery or taken to radiotherapy, presented with anemia. The hematological response due to the leukocyte/lymphocyte index (L/L) is increased at the end of treatment, possibly due to inflammatory processes generated by cancer, and baseline overweight and obesity. Patients with biochemical relapse exhibit a higher platelet count, suggesting that these cells could participate in the recurrence process and in metastasis (78%) in these patients. The coagulation index (INR) could be an indicator of the platelet response to be considered during the treatment and monitoring of patients. Full article

Immune-related hepatitis (irH) is a fairly frequent complication of immune checkpoint inhibitors (ICIs). Its management is generally based on withholding ICIs and on the rapid initiation of corticosteroids, which is successful in 63 to 96% of cases. Mycofenolate mofetil (MMF) is accepted as a second-line immunosuppressant in the case of the failure of corticosteroids. In rare cases, though, irH is also resistant to MMF and may lead to liver failure. There are no standard third-line treatments and current guidelines are based on a limited number of case reports. We present a case of a metastatic melanoma patient with an immune-related hepatitis refractory to corticosteroids and MMF, that was successfully reversed with tacrolimus. Unfortunately, this was complicated with a serious infection and progressive disease, which illustrates the complexity of treatment of steroid-refractory immunotherapy-related adverse events. Furthermore, we provided a literature review regarding the management of steroid-refractory hepatitis and proposed a strategy to circumvent the current uncertainties in the management of steroid-refractory irH. Full article

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a significant impact on the world’s demographics, resulting in over 6 million deaths globally. COVID-19 has been associated with a variety of disease manifestations in various organ systems, including kidney disease, in addition to pulmonary manifestations. Infection with SARS-CoV-2 can not only cause new kidney damage but also make treatment and care more difficult, as well as increase mortality in people who already have kidney problems. COVID-19 is indeed associated with a variety of renal pathologies, such as acute tubular necrosis, proteinuria, hematuria, and thrombosis complications. Cytokine storms, hypoxemia, direct viral invasion via angiotensin-converting enzyme 2 and cathepsin L, electrolyte imbalance, and fever are among the pathophysiological mechanisms underlying these clinical symptoms. Over the last two years, many COVID-19 vaccines have been discovered. However, there have been a few case reports of AKI, AKD, proteinuria, edema, gross hematuria, and other renal side effects that necessitated hospitalization after receiving COVID-19 vaccinations. Thus, the current review aimed to evaluate COVID-19-induced kidney dysfunction in terms of clinical features, pathogenesis, long-term outcomes, and vaccine harms based on the most up-to-date findings. Full article

Older adults with dementia present an increased risk of mortality due to seasonal influenza. Despite concerning evidence, the influenza vaccination program has been unsuccessful, with low rates of uptake in Italian people ≥65 years. In addition, being vaccinated does not eliminate the risk of contracting a virus, especially by coming into close contact with other possibly unvaccinated people, such as family caregivers in the home environment. Therefore, the refusal of family caregivers to get vaccinated for seasonal influenza could have dire consequences for their relatives with dementia. The aims of this study were to investigate the predictive role of the Theory of Planned Behavior model (TPB) and past vaccination behavior on the intention to receive a seasonal influenza vaccine among family caregivers of people with dementia. Data were collected from seventy-one respondents during July–September 2021 using a cross-sectional web-based survey design. Results of hierarchical binary logistic regression showed that TPB (i.e., attitudes towards vaccination, subjective norms, and perceived behavioral control) explained 51.6% of the variance in intention to receive a seasonal influenza vaccine; past vaccination behavior increased this to 58.8%. In conclusion, past vaccination behavior and the theory of planned behavior variables effectively predict influenza vaccine willingness of family caregivers of people with dementia and should be targeted in vaccination campaigns. Full article

Cancer stem cells (CSCs) are the cells in a primary tumor that have the opportunity to self-renew as well as differentiate into certain cell types, thus forming a mixed tumor. CSCs have been shown to be involved in every aspect of cancer development, including tumor initiation, proliferation, and metastatic activity; they are also involved in chemotherapeutic drug resistance and the recurrence of certain cancers. Based on these capabilities, CSCs have been explored as the next target for the treatment and management of cancer. Salinomycin (SAL), a polyether ionophore antibiotic being used in the poultry industry, was identified as a powerful anti-cancer compound that possesses broad-spectrum activities, especially against CSCs. Here we point out the noteworthy work reported on SAL’s mechanism of action, anticancer activities, toxicity, and clinic applications. In addition, SAL derivatives synthesized by different research groups and their biological activity will also be highlighted. Full article

Preeclampsia is an obstetric pathology with striking similarities to COVID-19. The renin-angiotensin system plays a key role in the pathogenesis of both diseases. This report reviews the pharmacological strategies that have been suggested for the prevention and treatment of preeclampsia and that are potentially useful also in the treatment of COVID-19. Of note, both pathologies have in common an Angiotensin II-mediated endothelial dysfunction secondary to an angiogenic imbalance, with effects on vasculature, coagulation, and inflammation. These considerations are drawn from cases of the initial SARS-CoV-2 primary infection and may not apply to more recent SARS-CoV-2 variants or infections after COVID vaccination. The treatment options discussed included albumin infusion, aspirin, corticosteroids, the monoclonal antibody eculizumab, hydroxychloroquine, low molecular weight heparin, magnesium, melatonin, metformin, nitric oxide, proton pump inhibitors, statins, therapeutic apheresis, and vitamin D. Full article

Malaria and HIV are geographically in the tropics and subtropics of the world, including sub-Saharan Africa. Understanding the overlapping effect of both infections, especially among pregnant women, is crucial in managing pregnant women during antenatal care visits, and postpartum babies. It was realized that the prevalence of malaria among HIV-positive pregnant women ranges between 31–61%, while for non-HIV infected pregnant women the prevalence still stands between 10 and 36%. Co-infection is between 0.52 and 56.3%. Even though the rate of mother-to-child transmission of HIV has dropped, MTCT of malaria still remains a problem. MTCT is associated with low birth-weight, anemia, and even immune dysregulation. The adoption of the Option B+ plan has proven to be effective in the fight against the MTCT of HIV. However, malaria in pregnancy still remains a problem. Concurrent administration of both antimalarial drugs and Cotrimozaxole to pregnant women is not recommended, because of the toxic effect of the interaction of both drugs. Nevertheless, studies looking at the effect of the current ART regimens on mothers and their children need to be carried out. Studies looking at exposed children over a longer period of time, to determine their susceptibility to malaria infection and also to monitor their immune response to malaria over time, are needed. Full article

Recently, some drugs were approved to control Monkeypox (MPX), among them tecovirimat. This was recently approved by regulatory agencies around the world, the paper of Zovi et al entitled Pharmacological Agents with Antiviral Activity against Monkeypox Infection highlight it as safe and effective, although the safety data are still not very robust. In this Comment, we present some theoretical evaluations of its safety, considering that for use in humans it is essential to have a rich scientific literature in the area. After a series of analyses, a potential risk of liver, respiratory and kidney damage was found in addition to carcinogenic potential. Thus, while we agree that there is a need for rapid responses to infection, we reinforce that well-designed and adequately powered studies should not only focus on investigating the pharmacological efficacy of tecovirimat but also demonstrate its safety in humans. Therefore, in this Comment, we present some concerns that may help in formulating a safer treatment for patients infected with Monkeypox virus (MPXV). Full article

Depression and obesity are highly comorbid with one another, with evidence of bidirectional causal links between each disorder and a shared biological basis. Genetic factors play a major role in influencing both the occurrence of comorbid depression and obesity, their courses, and their response to existing treatments. The current paper is a scoping review of studies that have evaluated the contribution of specific genetic variants to the comorbidity between obesity and depression. Based on a search of the PubMed and EMBASE databases, 28 studies were included in this review, covering 54 candidate genes. Positive associations were identified for 14 genetic loci (AKR1C2, APOA5, COMT, DAT1, FTO, KCNE1, MAOA, MC4R, MCHR2, NPY2R, NR3C1, Ob, PCSK9, and TAL1). Replicated findings across two or more independent samples were observed for the FTO and MC4R genes. Many of these gene products represent novel molecular targets for the pharmacological management of obesity that interact with each other and are not pharmacologically influenced by existing anti-obesity or antidepressant medications. The implications of these associations for future drug development are discussed, with an emphasis on recent evidence on the polygenic architecture of comorbid depression and obesity and on a precision-medicine approach to these conditions. Full article

Exacerbation of the vascular pathology in radiation retinopathy as a result of pre-existing diabetes has been recognized for many years, as reflected by clinical reports and a few early experimental studies. However, the underlying pathogenetic mechanisms for the synergistic interaction of radiation retinopathy (RR) and diabetic retinopathy (DR) have not been compared and evaluated for insight on this phenomenon. The present work draws attention to the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as common mediators of both conditions and sources of ongoing cellular injury in the radiation-induced bystander effect (RIBE) and the senescence-associated secretory phenotype (SASP). Chronic hyperglycemia-mediated oxidative stress and depleted antioxidant defense in diabetes, together with impaired DNA damage sensing and repair mechanisms, were identified as the primary elements contributing to the increased severity of RR in diabetic patients. We conclude that apart from strategic genetic mutations affecting the DNA damage response (DDR), diabetes represents the most significant common risk factor for vascular injury as a side effect of radiotherapy. Full article

Visceral pain is a unique clinical entity that lacks an effective and safe treatment. Proper preclinical models are essential for assessing new drugs developed for the treatment of this pathology. Few studies report that paclitaxel, an antineoplastic agent, can be used to induce visceral pain in laboratory animals. Our purpose was to investigate the reproducibility of these studies and to develop an animal method that would allow assessing consistent visceral pain. In this study, we used four doses of paclitaxel (3 mg × kg⁻¹; 5 mg × kg⁻¹; 10 mg × kg⁻¹ and 15 mg × kg⁻¹). Visceral pain was evaluated using a scale of abdominal pain immediately after the administration of a single dose of paclitaxel to rats. Tactile and thermal hypersensitivity were assessed using von Frey filaments and the tail flick test initially, at 24 h and 48 h after administration. Rats experienced visceral pain and mechanical and thermal hypersensitivity 24 h after the administration of paclitaxel. The intensity of the pain was increased in a dose-dependent manner with the highest intensity of effect being observed after the administration of a dose of 15 mg × kg⁻¹. Paclitaxel induces visceral pain. The dosage varies depending on the employed strain of rat. This method allows for assessing the efficacy of analgesics to be useful against visceral pain if the paclitaxel dose is adjusted accordingly to the animal strain. Full article

The periodontal disease etiology has been a demesne of scrupulous research, with a myriad of bacterial phylotypes inhabiting the periodontal pockets. The aim of our study was to assess the frequency of Filifactor alocis in type 2 diabetes mellitus (DM) subjects having a healthy periodontium (DH) or chronic periodontitis (DCP) and its correlation with clinical parameters and red complex bacteria. Polymerase chain reaction was carried out for the detection of F. alocis and red complex bacteria from subgingival plaque samples. The data were analyzed using Fisher’s Exact Test and Pearson’s chi-square test. A p value < 0.05 was considered statistically significant. F. alocis was detected at considerably higher levels in DCP (p < 0.05). F. alocis presence was also positively correlated with T. forsythia detection and the clinical parameters PD and CAL (p < 0.05). Subjects with good glycemic control showed a considerably lower detection of F. alocis as compared to fair- and poor-glycemic-control subjects. This is the first paper reporting the co-occurrence of F. alocis and T. forsythia in diabetic subjects with chronic periodontitis. These findings show that F. alocis can play an important role in establishing synergistic collaborations with other pathogenic oral microorganisms and speeding up the course of periodontal disease in diabetics. Full article