Changes in Expression of Specific mRNA Transcripts after Single- or Re-Irradiation in Mouse Testes

Alkylating agents and irradiation induce testicular damage, which results in prolonged azoospermia. Even very low doses of radiation can significantly impair testis function. However, re-irradiation is an effective strategy for locally targeted treatments and the pain response and has seen important advances in the field of radiation oncology. At present, little is known about the relationship between the harmful effects and accumulated dose of irradiation derived from continuous low-dose radiation exposure. In this study, we examined the levels of mRNA transcripts encoding markers of 13 markers of germ cell differentiation and 28 Sertoli cell-specific products in single- and re-irradiated mice. Our results demonstrated that re-irradiation induced significantly decreased testicular weights with a significant decrease in germ cell differentiation mRNA species (Spo11, Tnp1, Gfra1, Oct4, Sycp3, Ddx4, Boll, Crem, Prm1, and Acrosin). In the 13 Sertoli cell-specific mRNA species decreased upon irradiation, six mRNA species (Claudin-11,Espn, Fshr, GATA1, Inhbb, and Wt1) showed significant differences between single- and re-irradiation. At the same time, different decreases in Sertoli cell-specific mRNA species were found in single-irradiation (Aqp8, Clu, Cst12, and Wnt5a) and re-irradiation (Tjp1, occludin,ZO-1, and ZO-2) mice. These results indicate that long-term aspermatogenesis may differ after single- and re-irradiated treatment.

Changes in Expression of Specific mRNA Transcripts after Single- or Re-Irradiation in Mouse Testes

Alkylating agents and irradiation induce testicular damage, which results in prolonged azoospermia. Even very low doses of radiation can significantly impair testis function. However, re-irradiation is an effective strategy for locally targeted treatments and the pain response and has seen important advances in the field of radiation oncology. At present, little is known about the relationship between the harmful effects and accumulated dose of irradiation derived from continuous low-dose radiation exposure. In this study, we examined the levels of mRNA transcripts encoding markers of 13 markers of germ cell differentiation and 28 Sertoli cell-specific products in single- and re-irradiated mice. Our results demonstrated that re-irradiation induced significantly decreased testicular weights with a significant decrease in germ cell differentiation mRNA species (Spo11, Tnp1, Gfra1, Oct4, Sycp3, Ddx4, Boll, Crem, Prm1, and Acrosin). In the 13 Sertoli cell-specific mRNA species decreased upon irradiation, six mRNA species (Claudin-11, Espn, Fshr, GATA1, Inhbb, and Wt1) showed significant differences between single- and re-irradiation. At the same time, different decreases in Sertoli cell-specific mRNA species were found in single-irradiation (Aqp8, Clu, Cst12, and Wnt5a) and re-irradiation (Tjp1, occludin, ZO-1, and ZO-2) mice. These results indicate that long-term aspermatogenesis may differ after single- and re-irradiated treatment.

An Update on Psychopharmacological Treatment of Autism Spectrum Disorder

While behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD.

Role of Biomarkers in the Integrated Management of Melanoma

Melanoma, which is an aggressive skin cancer, is currently the fifth and seventh most common cancer in men and women, respectively. The American Cancer Society reported that approximately 106,110 new cases of melanoma were diagnosed in the United States in 2021, with 7,180 people dying from the disease. This information could facilitate the early detection of possible metastatic lesions and the development of novel therapeutic techniques for melanoma. Additionally, early detection of malignant melanoma remains an objective of melanoma research. Recently, melanoma treatment has substantially improved, given the availability of targeted treatments and immunotherapy. These developments have highlighted the significance of identifying biomarkers for prognosis and predicting therapy response. Biomarkers included tissue protein expression, circulating DNA detection, and genetic alterations in cancer cells. Improved diagnostic and prognostic biomarkers are becoming increasingly relevant in melanoma treatment, with the development of newer and more targeted treatments. Here, the author discusses the aspects of biomarkers in the real-time management of patients with melanoma.

So-Called Serous Carcinoma of the Uterine Cervix with BRCA2 Mutation: Case Report and Review of the Literature

Serous carcinoma of the uterine cervix (SCUC) is now believed to be a morphological variant of an HPV-associated endocervical adenocarcinoma or a metastasis from a serous carcinoma of the upper tract. In terms of mutational status as detected by next-generation sequencing (NGS), this controversial entity has not been characterized yet. We describe the case of a patient with a carcinoma categorized as stage IVB SCUC, initially treated with carboplatin, paclitaxel, and bevacizumab, followed by maintenance with bevacizumab. After locoregional progression, radiotherapy was administered. Unfortunately, further progression was observed, and carboplatin was resumed. Considering the presence of a <i>BRCA2</i> mutation as detected by NGS, treatment with a PARP inhibitor (olaparib) was decided and allowed disease control for 6 months. We believe that <i>BRCA</i> mutation may be systematically searched in patients suffering from carcinomas formerly referred to as SCUC and that targeted treatments should be considered.

Combination of Modern Radiotherapy and New Targeted Treatments for Breast Cancer Management

Background: The objective of the present study was to review the essential knowledge about the combinations of the most commonly used or under development targeted treatments and radiation therapy (RT). Methods: Preclinical and clinical studies investigating this combination were extensively reviewed. Results: Several studies showed that the combination of RT and tamoxifen increased the risk of radiation-induced pulmonary toxicity; therefore, both modalities should not be given concomitantly. The combination of HER2 inhibitors (trastuzumab, pertuzumab) and RT seems to be safe. However, trastuzumab emtansine (T-DM1) should not be administered concurrently with brain RT since this combination could increase the risk of brain radionecrosis. The combination of RT and other new target treatments such as selective estrogen receptor degradants, lapatinib, cell cycle inhibitors, immune checkpoint inhibitors, or molecules acting on DNA damage repair seems feasible but was essentially evaluated on retrospective or prospective studies with a small number of patients. Furthermore, there is considerable heterogeneity among these studies regarding the dose and fractionation of radiation, the dosage of drugs, and the sequence of treatments used. Conclusions: The combination of RT with most targeted therapies for BC appears to be well-tolerated, but these results need to be confirmed in prospective randomized studies.

Integrated Tick Management in Guilford, CT: Fipronil-Based Rodent-Targeted Bait Box Deployment Configuration and Peromyscus leucopus (Rodentia: Cricetidae) Abundance Drive Reduction in Tick Burdens

Integrated tick management (ITM) is a comprehensive strategy used to reduce presence of ticks and their associated pathogens. Such strategies typically employ a combination of host and non-host targeted treatments which often include fipronil-based, rodent-targeted bait boxes. Bait boxes target small-bodied rodents, specifically white-footed mice (Peromyscus leucopus Rafinesque) that not only play a crucial role in the blacklegged tick (Ixodes scapularis Say (Ixodida: Ixodidae)) life cycle, but also in the transmission of numerous pathogens, primarily Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt & Brenner (Spirochaetales: Spirochaetaceae), the causal agent of Lyme disease. This study aimed to determine the effect of bait box deployment configuration on tick burden reduction while also further exploring bait consumption and P. leucopus abundances as measures of bait box usage and effectiveness. Boxes were deployed on nine properties within each of six neighborhoods (n = 54) in two different configurations: grid and perimeter. Multiple factors were analyzed as potential predictors for reduction in tick burdens using a backward stepwise selection procedure. Results confirmed the perimeter configuration was a more effective deployment strategy. In addition, overall P. leucopus abundance was a significant predictor of tick burden reduction while bait consumption was not. These findings not only further support the recommended perimeter deployment configuration but provide insight into effective utilization in areas of high P. leucopus abundance. The identification of this significant relationship, in addition to configuration, can be utilized by vector control professionals and homeowners to make informed decisions on bait box placement to make sustained impacts on the I. scapularis vector and associated pathogens within an ITM framework.

Polymorphonuclear Cells Show Features of Dysfunctional Activation During Fatal Sepsis

Sepsis and septic shock remain leading causes of morbidity and mortality for patients in the intensive care unit. During the early phase, immune cells produce various cytokines leading to prompt activation of the immune system. Polymorphonuclear leukocytes (PMNs) respond to different signals producing inflammatory factors and executing their antimicrobial mechanisms, resulting in the engulfment and elimination of invading pathogens. However, excessive activation caused by various inflammatory signals produced during sepsis progression can lead to the alteration of PMN signaling and subsequent defects in their functionality. Here, we analyzed samples from 34 patients in septic shock, focusing on PMNs gene expression and proteome changes associated with septic shock. We revealed that, compared to those patients who survived longer than five days, PMNs from patients who had fulminant sepsis were characterized by a dysfunctional hyper-activation, show altered metabolism, and recent exit from the cell cycle and signs of cellular lifespan. We believe that this multi-omics approach, although limited, pinpoints the alterations in PMNs’ functionality, which may be rescued by targeted treatments.

Gut Microbiome and Its Role in the Pathophysiology of Irritable Bowel Syndrome

Irritable bowel syndrome is the most common functional gastrointestinal disorder, affecting up to 9% individuals globally. Although the etiology of this syndrome is likely heterogenous, it presents with its hallmark symptoms of abdominal pain and altered intestinal motility. Moreover, it is considered to be a disorder of the gut-brain interaction, and the microbiome has often been implicated as a central player in its pathophysiology. Patients with irritable bowel syndrome display altered composition and function of the gut microbiota compared to healthy controls. Microbiome directed therapies, such as probiotics, antibiotics and fecal microbiome transplantation, appear to be beneficial for both gut symptoms and psychiatric comorbidities. This review aims to recapitulate the available literature on the microbiome contribution to the pathophysiology and symptoms presentation of irritable bowel syndrome, as well as the current literature on microbiome-targeted treatments for this disease.