Therapy Approaches Research Articles

Audiophonologopedic Telerehabilitation: Advantages and Disadvantages from User Perspectives.

Technological advancements and the COVID-19 pandemic have highlighted the importance of digital tools for patient care and rehabilitation. This study explores user perspectives on telerehabilitation, comparing it to traditional methods and identifying criteria for determining its suitability for different patients and clinical conditions. This study was carried out during the period of May-September 2021. Questionnaires were administered to 48 users in rehabilitation for audiophonologopedic and neurodevelopmental disorders in three rehabilitation centres in central Italy. The user responses predominantly emphasize the benefits of time saving (68.75%) and cost-efficiency (37.5%), specifically regarding time saving due to travel and expenses incurred to go to where the therapy is carried out. The disadvantages include increased distraction (60.42%) in following the instructions remotely and logistic problems (39.58%). Patients with hearing loss were subjected to a larger number of telerehabilitation sessions, positively rating this alternative method. Patients with speech and language delay and autism spectrum disorder (ASD) prefer traditional treatment. This study reveals a favourable perception of telerehabilitation as a therapy approach to be regarded as a supplement or temporary option to the irreplaceable face-to-face one. More research, as well as a larger sample sizes, will be useful to increase the significance of the correlations reported in this study.

Successful Treatment of Granuloma Annulare with Tapinarof 1% Cream: A Case Report

Peritoneal Metastasis (PM) is a common site of dissemination of gastric cancer. PM remains a major cause of mortality and is associated with poor prognosis. For this reason the last 30 years the treatment of peritoneal disease is an important target for improving survival. The therapeutic approaches of locoregional therapy for GCPM include different types of surgery and different types of intraperitoneal chemotherapy. This review presents an overview of these modalities and summarizes the evolution of management the last years. It highlights in controversial options which existing in literature and focuses in the ongoing clinical trials that will help establish the role of locoregional treatments in GCPM.

THE PROFILE AND CLINICAL EVIDENCE OF EFFECTIVENESS OF OLAPARIB IN TRIPLENEGATIVE BREAST CANCER: A REVIEW

Triple-negative breast cancer (TNBC) is one of the most common malignancies in women. The majority of patients with TNBC have a poor prognosis. The main objective of this study is to review the profile and clinical evidence of the effectiveness of Olaparib in treating TNBC. A literature search was conducted using multiple electronic databases, including PubMed, Google Scholar, JSTOR, and Scopus. The search was focused on articles published up to June 2024, ensuring the inclusion of the latest and relevant studies. The primary objective was to investigate the mechanism of action, toxicity profile, resistance mechanisms, and therapeutic effectiveness of olaparib in the treatment of TNBC, regardless of their prior chemotherapy treatment for metastatic breast cancer, prior platinum-based chemotherapy, or usage of cyclin-dependent kinase 4/6 inhibitors (Balmana et al., 2022). The results of this research suggest that the pharmacological efficacy and safety characteristics of this medication in TNBC patients are similar to those reported in the OlympiAD study. Furthermore, stratification of patients for this medication is possible due to the diagnostic techniques that can predict the presence of the BRCA mutation in order to optimize its efficacies. Additionally, developing and validating new biomarkers beyond BRCA mutations for patient stratification could optimize targeted therapy approaches.

Viral Factors in Modulation of Host Immune Response: A Route to Novel Antiviral Agents and New Therapeutic Approaches.

Viruses utilize host cells at all stages of their life cycle, from the transcription of genes and translation of viral proteins to the release of viral copies. The human immune system counteracts viruses through a variety of complex mechanisms, including both innate and adaptive components. Viruses have an ability to evade different components of the immune system and affect them, leading to disruption. This review covers contemporary knowledge about the virus-induced complex interplay of molecular interactions, including regulation of transcription and translation in host cells resulting in the modulation of immune system functions. Thorough investigation of molecular mechanisms and signaling pathways that are involved in modulating of host immune response to viral infections can help to develop novel approaches for antiviral therapy. In this review, we consider new therapeutic approaches for antiviral treatment. Modern therapeutic strategies for the treatment and cure of human immunodeficiency virus (HIV) are considered in detail because HIV is a unique example of a virus that leads to host T lymphocyte deregulation and significant modulation of the host immune response. Furthermore, peculiarities of some promising novel agents for the treatment of various viral infections are described.

Neomorphic IDH Heterodimer Mutants: An Underestimated Point in Cancer Pathogenesis.

Mutations in an essential metabolic enzyme, isocitrate dehydrogenase (IDH), were found in many cancers. The impact of IDH1 and IDH2 proteoforms mutations can vary and de-pend on the cancer type and other genetic alterations. The wild-type IDH1/2 consists of two identical subunits, but the mutant enzyme is a heterodimer of mutant and wild-type subunits, while the mutant homodimer loses its catalytic activity. Thus, the balance of expression of wild-type and mutant proteoforms directly affects enzyme neomorphic activity, cell metabolic por-trait, and, therefore, cell survival and proliferation rates. Here, we generalize the influence of the presence of IDH mutations and the expression of mutant and wild-type proteoforms for various nosologies to demonstrate the deficiency in knowledge about the mutual distribution of the pro-teoforms in cancer cells. The review is supplemented with a brief description of IDH mutations' role in cell metabolic reprogramming and a summary of methods for IDH mutation detection. Eventually, we highlight the necessity of assessing the expression of wild-type and mutated IDH quantitatively, which can help create and deliver personalized approaches for tumor therapy.

Blood-tumor barrier in focus - investigation of glioblastoma-induced effects on the blood-brain barrier.

Glioblastoma (GBM) is the most prevalent, malignant, primary brain tumor in adults, characterized by limited treatment options, frequent relapse, and short survival after diagnosis. Until now, none of the existing therapy and treatment approaches have proven to be an effective cure. The availability of predictive human blood-tumor barrier (BTB) test systems that can mimic in-vivo pathophysiology of GBM would be of great interest in preclinical research. Here, we present the establishment of a new BTB in-vitro test system combining GBM spheroids and BBB models derived from human induced pluripotent stem cells (hiPSCs). We co-cultured hiPSC-derived brain capillary endothelial-like cells (iBCECs) with GBM spheroids derived from U87-MG and U373-MG cell lines in a cell culture insert-based format. Spheroids were monitored over 168hours (h) of culture, characterized for GBM-specific marker expression and treated with standard chemotherapeutics to distinguish inhibitory effects between 2D mono-culture and 3D spheroids. GBM-induced changes on iBCECs barrier integrity were verified via measurement of transendothelial electrical resistance (TEER), immunocytochemical staining of tight junction (TJ) proteins claudin-5 and occludin as well as the glucose transporter-1 (Glut-1). GBM-induced secretion of vascular endothelial growth factor (VEGF) was additionally quantified. Our hypothesis was validated by reduced expression of TJ proteins, occludin and claudin-5 together with significant barrier breakdown in iBCECs after only 24h of co-culture, demonstrated by reduction in TEER from 1313 ± 265 Ω*cm2 to 712 ± 299 Ω*cm2 (iBCECs + U87-MG) and 762 ± 316 Ω*cm2 (iBCECs + U373-MG). Furthermore, 3D spheroids show more resistance to standard GBM chemotherapeutics in-vitro compared to 2D cultures. We demonstrate the establishment of a simplified, robust in-vitro BTB test system, with potential application in preclinical therapeutic screening and in studying GBM-induced pathological changes at the BBB.

Identification of novel PHGDH inhibitors based on computational investigation: an all-in-one combination strategy to develop potential anti-cancer candidates.

Biological studies have elucidated that phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the serine synthesis pathway in humans that is abnormally expressed in numerous cancers. Inhibition of the PHGDH activity is thought to be an attractive approach for novel anti-cancer therapy. The development of structurally diverse novel PHGDH inhibitors with high efficiency and low toxicity is a promising drug discovery strategy. A ligand-based 3D-QSAR pharmacophore model was developed using the HypoGen algorithm methodology of Discovery Studio. The selected pharmacophore model was further validated by test set validation, cost analysis, and Fischer randomization validation and was then used as a 3D query to screen compound libraries with various chemical scaffolds. The estimated activity, drug-likeness, molecular docking, growing scaffold, and molecular dynamics simulation processes were applied in combination to reduce the number of virtual hits. The potential candidates against PHGDH were screened based on estimated activity, docking scores, predictive absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties, and molecular dynamics simulation. Finally, an all-in-one combination was employed successfully to design and develop three potential anti-cancer candidates.

Proteomic Investigation of Immune Checkpoints and Some of Their Inhibitors.

Immune checkpoints are crucial molecules for the maintenance of antitumor immune responses. The activation or inhibition of these molecules is dependent on the interactions between receptors and ligands; such interactions can provide inhibitory or stimulatory signals to the various components of the immune system. Over the last 10 years, the inhibition of immune checkpoints, such as cytotoxic T lymphocyte antigen-4, programmed cell death-1, and programmed cell death ligand-1, has taken a leading role in immune therapy. This relatively recent therapy regime is based on the use of checkpoint inhibitors, which enhance the immune response towards various forms of cancer. For a subset of patients with specific forms of cancer, these inhibitors can induce a durable response to therapy; however, the medium response rate to such therapy remains relatively poor. Recent research activities have demonstrated that the disease response to this highly promising therapy resembles the response of many forms of cancer to chemotherapy, where an encouraging initial response is followed by acquired resistance to treatment and progress of the disease. That said, these inhibitors are now used as single agents or in combination with chemotherapies as first or second lines of treatment for about 50 types of cancer. The prevailing opinion regarding immune therapy suggests that for this approach of therapy to deliver on its promise, a number of challenges have to be circumvented. These challenges include understanding the resistance mechanisms to immune checkpoint blockade, the identification of more efficient inhibitors, extending their therapeutic benefits to a wider audience of cancer patients, better management of immune-related adverse side effects, and, more urgently the identification of biomarkers, which would help treating oncologists in the identification of patients who are likely to respond positively to the immune therapies and, last but not least, the prices of therapy which can be afforded by the highest number of patients. Numerous studies have demonstrated that understanding the interaction between these checkpoints and the immune system is essential for the development of efficient checkpoint inhibitors and improved immune therapies. In the present text, we discuss some of these checkpoints, their inhibitors, and some works in which mass spectrometry-based proteomic analyses were applied.

Proteolysis targeting chimera extracellular vesicles for therapeutic development treating triple negative breast cancer.

Proteolysis targeting chimeras (PROTACs) are an emerging targeted cancer therapy approach, but wide-spread clinical use of PROTAC is limited due to poor cell targeting and penetration, and instability in vivo. To overcome such issues and enhance the in vivo efficacy of PROTAC drugs, microfluidic droplet-based electroporation (µDES) was developed as a novel extracellular vesicle (EVs) transfection system, which enables the high-efficient PROTAC loading and effective delivery in vivo. Our previously developed YX968 PROTAC drug had shown the selectively degradation of HDAC3 and 8, which effectively suppresses the growth of breast tumor cell lines, including MDA-MB-231 triple negative breast cancer (TNBC) line, via dual degradation without provoking a global histone hyperacetylation. In this study, we demonstrated that µDES-based PROTAC loading in EVs significantly enhanced therapeutic function of PROTAC drug in vivo in the TNBC breast tumor mouse model. NSG mice with pre-established MDA-MB-231 tumors and treated with intraperitoneal injection of EVs for tumor inhibition study, which showed significantly higher HDAC 3 and 8 degradation efficiency and tumor inhibition than PROTAC only group. The liver, spleen, kidney, lung, heart, and brain were collected for safety testing, which exhibited improved toxicity. The EV delivery of PROTAC drug enhances drug stability and bioavailability in vivo, transportability, and drug targeting ability, which fills an important gap in current development of PROTAC therapeutic functionality in vivo and clinical translation. This novel EV-based drug transfection and delivery strategy could be applicable to various therapeutics for enhancing in vivo delivery, efficacy, and safety.

MAGICAL: A multi-class classifier to predict synthetic lethal and viable interactions using protein-protein interaction network.

Synthetic lethality (SL) and synthetic viability (SV) are commonly studied genetic interactions in the targeted therapy approach in cancer. In SL, inhibiting either of the genes does not affect the cancer cell survival, but inhibiting both leads to a lethal phenotype. In SV, inhibiting the vulnerable gene makes the cancer cell sick; inhibiting the partner gene rescues and promotes cell viability. Many low and high-throughput experimental approaches have been employed to identify SLs and SVs, but they are time-consuming and expensive. The computational tools for SL prediction involve statistical and machine-learning approaches. Almost all machine learning tools are binary classifiers and involve only identifying SL pairs. Most importantly, there are limited properties known that best describe and discriminate SL from SV. We developed MAGICAL (Multi-class Approach for Genetic Interaction in Cancer via Algorithm Learning), a multi-class random forest based machine learning model for genetic interaction prediction. Network properties of protein derived from physical protein-protein interactions are used as features to classify SL and SV. The model results in an accuracy of ~80% for the training dataset (CGIdb, BioGRID, and SynLethDB) and performs well on DepMap and other experimentally derived reported datasets. Amongst all the network properties, the shortest path, average neighbor2, average betweenness, average triangle, and adhesion have significant discriminatory power. MAGICAL is the first multi-class model to identify discriminatory features of synthetic lethal and viable interactions. MAGICAL can predict SL and SV interactions with better accuracy and precision than any existing binary classifier.

Green-synthesized Metal Nanoparticles for Cancer Diagnosis and Treatment: A Critical Review

: The utilization of chemotherapy remains an established therapeutic strategy in the ongoing fight against cancer. Nevertheless, it has been impeded by the occurrence of several fatal adverse reactions caused by non-specific toxicity often associated with chemotherapy. Nanotechnology is an emerging field of research that is experiencing rapid growth and is widely recognized as a highly promising approach for advanced cancer therapy. Biosynthesized green nanomaterials are emerging as promising tools for cancer treatment and diagnosis. Metal nanoparticles have been developed for use in several applications, including magnetically sensitive medication delivery, photothermal treatment, and photoimaging. Nanomaterials containing metals, such as iron, cobalt, and silver, which are generated from various bio-sources, have been described. The boundless capabilities of nanoparticles have already had a profound impact on human existence. Nevertheless, the potential adverse effects of nanoparticles on human health have consistently instilled apprehension. A thorough investigation of the toxicity and intricate nature of nanomaterials has facilitated the emergence of nanotoxicology, a field that examines the fundamental origins of these problems. The introduction of green chemistry principles has aimed to provide safer techniques for the production and management of nanomaterials, resulting in the emergence of green nanotechnology. This review article highlights the potential uses of green nanotechnology for the detection and management of tumors, including the challenges they face in reaching clinical trials.

Efficacy and Safety of Cryoablation in Barrett's Esophagus and Comparison with Radiofrequency Ablation: A Meta-Analysis.

The mainstay approach in endoscopic eradication therapy (EET) for dysplastic Barrett's esophagus (BE) includes the endoscopic resection of visible lesions, accompanied by ablation of the residual metaplastic epithelium. Cryoablation therapy is one such emerging ablation technique in this field. This systematic review with a meta-analysis aims to accumulate pooled data on cryoablation performance in the treatment of patients with BE and to compare this technique to the standard of care radiofrequency ablation (RFA). The MEDLINE, Cochrane, and Scopus databases were searched until June 2024 for studies evaluating BE management using cryoablation for cumulative results. The primary outcome was the complete eradication of dysplasia (CED) and intestinal metaplasia (CEIM) in BE compared to RFA, while secondary outcomes included the respective pooled rates using cryoablation, recurrence, and adverse events, with a separate analysis for strictures. The meta-analyses were based on a random-effects model, and the results were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses by type of cryoablation were also performed. Twenty-three studies (1604 patients) were finally included, four of which were comparative. CED and CEIM did not differ significantly between cryoablation and RFA [OR= 0.95 (95%CI: 0.50-1.81) and OR = 0.57 (95%CI: 0.20-1.63), respectively)]. The pooled rates of CED, CEIM, and recurrence after cryoablation were 84.2% (95%CI: 79.1-89.3), 64.1% (95%CI: 49.2-79.0), and 8.3% (95%CI: 4.7-11.9), accompanied by high rates of heterogeneity. Adverse events were noted in 14.5% (95%CI: 9.9-19.2) of cases, and 6.5% (95%CI: 4.1-9.0) developed strictures. In the subgroup analysis, the cryoballoon achieved a reduction in heterogeneity in CED, adverse events, and stricture formation, whereas spray catheters provided homogenous results in terms of recurrence. Cryoablation provides equal outcomes compared to RFA in the treatment of patients with BE, with the cryoballoon achieving relatively homogenous rates of CED and adverse events.

Development of a Multiplex Immunofluorescence Assay for Tumor Microenvironment Studies of Human and Murine Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Checkpoint inhibitor immunotherapy plays an essential role in management of advanced MCC; however, predictors of immunotherapy response remain poorly defined. Syngeneic mouse models suitable for testing novel immunotherapy and combination therapy approaches are likely to soon become available and will require assays for evaluating the tumor microenvironment (TME). Multiplex immunofluorescence (mIF) is a powerful approach to characterize the TME for understanding immunotherapy responses and immune surveillance. In this method article, we provide detailed instructions on assay development for mIF, using as examples 2 new mIF panels for TME investigations of human and murine MCC tumors. Specifically, we demonstrate panels that allow simultaneous visualization of the Merkel cell master transcription factor SOX2 for tumor cell identification, alongside T-cell markers (CD3, CD8, and FOXP3), macrophage markers (F4/80 for mouse and CD163 for human tumors), together with the checkpoint marker PD-L1 for human tumors, and the myeloid-derived suppressor cell marker Arg1 for mouse tumors. We provide detailed protocols for investigators to incorporate these mIF panels into their investigations of human and murine MCC. We also provide fundamental guidance for mIF assay development that will be broadly useful for investigators who consider modifying the panels presented in this study or developing their own mIF panels.

New therapeutic approaches for non-muscle invasive bladder cancer-is organ preservation also possible after BCG (Bacillus Calmette Guérin)?

Bacillus Calmette-Guérin (BCG) therapy is the standard of care in the treatment of high-risk non-muscle invasive bladder cancer (NMIBC). In the absence of aresponse to BCG and persistent high-grade disease, cystectomy is recommended depending on the clinical risk. Avariety of targeted therapy approaches, which aim at immune- and gene-based molecular targets, such as PD-(L)1 and FGFR, are currently being investigated in randomized studies for BCG-unresponsive NMIBC. Furthermore, novel forms of application for instillation therapy, such as the TAR device, in combination with gemcitabine or erdafitinib are being investigated in clinical trials in order to extend the duration of action of the active substance on the urothelium. Thus, there are now many developments that could make bladder-preserving therapy with comparable survival data possible as an alternative to BCG or in the event of BCG failure. In the future, it will be necessary to clarify how BCG response can be predicted by using molecular markers and how to define risk groups that should primarily be given an alternative therapy to BCG.

Small Cell Bladder Cancer: Treatment Patterns for Local Disease and Associated Outcomes. A Retrospective Cohort Study

BackgroundSmall cell bladder cancer (SCBC) is a rare histologic subtype with relative paucity of data regarding treatment response and outcomes. We reviewed 2 databases to compare outcomes in patients with localized SCBC treated with cystectomy versus concurrent chemoradiotherapy (CCRT). We hypothesized that survival would be similar with these therapy approaches. MethodsWe retrospectively reviewed our institutional and SEER-Medicare databases to identify patients with SCBC. Overall survival (OS) was determined from the date of diagnosis to last follow-up/death. For those with nonmetastatic disease, a multivariate Cox analysis was used to compare locoregional therapy with neoadjuvant chemotherapy (NAC) + cystectomy versus CCRT. ResultsWe identified 53 patients in our institutional database and 1166 patients in SEER-Medicare with localized SCBC. Median OS (mOS) with NAC + cystectomy was 46 months (95% CI, 21-72) and 45 months (95% CI, 0-104) in the institutional and SEER-Medicare databases, respectively, whereas mOS with CCRT was 26 months (95% CI, 5-47) and 23 months (95% CI, 18-28) in the 2 series, respectively. In multivariate analysis, NAC followed by cystectomy was associated with an approximately 30% reduction in mortality compared to CCRT in both institutional and national databases but did not reach statistical significance (Institution HR 0.71, 95% CI, 0.22-2.4, P = .58; SEER HR 0.73, 95% CI, 0.49-1.08; P = .11). ConclusionsSCBC is very aggressive with limited survival observed in our institutional and SEER-Medicare datasets regardless of locoregional therapy used. There is an unmet need to define the optimal locoregional therapy for nonmetastatic stage and identify novel therapeutic targets.

Evaluating precision medicine approaches for gene therapy in patient-specific cellular models of Bietti crystalline dystrophy.

Patient-specific induced pluripotent stem cell-derived (iPSC-derived) cell lines allow for therapies to be tailored to individual patients, increasing therapeutic precision and efficiency. Bietti crystalline dystrophy (BCD) is a rare blinding disease estimated to affect about 67,000 individuals worldwide. Here, we used iPSC-derived retinal pigment epithelium (iRPE) cells from patients with BCD to evaluate adeno-associated virus-mediated (AAV-mediated) gene augmentation therapy strategies. We found that BCD iRPE cells were vulnerable to blue light-induced oxidative stress and that cellular phenotype can be quantified using 3 robust biomarkers: reactive oxygen species (ROS), 4-hydroxy 2-nonenal (4-HNE) levels, and cell death rate. Additionally, we demonstrated that AAV-mediated gene therapy can significantly reduce light-induced cell death in BCD iRPE cells. This is the first proof-of-concept study to our knowledge to show that AAV-CYP4V2 gene therapy can be used to treat light-induced RPE damage in BCD. Furthermore, we observed significant variability in cellular phenotypes among iRPE from patients with BCD of divergent mutations, which outlined genotype-phenotype correlations in BCD patient-specific cell disease models. Our results reveal that patient-specific iRPE cells retained personalized responses to AAV-mediated gene therapy. Therefore, this approach can advance BCD therapy and set a precedent for precision medicine in other diseases, emphasizing the necessity for personalization in healthcare to accommodate individual diversity.

Relationship Between Treatment Hours of Selected Disciplines And Change in Pain Impact During the Year Following Referral to an Interdisciplinary Pain Management Center: A Latent Class Analysis.

Introduction: Pain management clinics differ in treatments offered, and little evidence exists regarding which combinations of therapies result in best outcomes. This study analyzed clinical encounters and pain outcomes data for associations between treatment composition and outcomes. Methods: Retrospective observational study of 2,142 predominantly active-duty US service members referred to an interdisciplinary pain management center between 2014 and 2021. Latent class analysis was used to identify treatment groups with distinct outcome patterns during the year following initial assessment. The primary outcome measure was the National Institutes of Health Task Force on Research Standards for Chronic Low-Back Pain impact score. Results: Four distinct treatment groups were identified: 1 group engaged in conventional medical therapies alone (n = 726, median 3.5 treatment hours), and 3 groups used a combination of conventional, psychological, rehabilitative, and complementary therapies, with different levels of treatment hours: low (n = 814, median 15.7 h), medium (n = 177, median 40.1 h), and high (n = 425, median 72.5 h). All groups showed significant improvement in pain impact score from baseline up to 9 months but not at 12 months following initial assessment. At the 6-month time point, the group with high multimodal treatment hours had the most improvement in pain impact (-3.1 [95% CI -3.8, -2.4]) compared with the group using only conventional therapies (-1.0 points [95% CI -1.8, -0.1]) or with low multimodal treatment hours (-1.3 points [95% CI -1.9, -0.7]). There were no between-group differences at the 9- or 12-month time points. Conclusion: These results suggest that a combination of pain therapy approaches results in greater reduction in pain impact than the use of conventional medical treatment alone for up to 6 months after initiating therapy and that there may be a threshold of treatment hours that must be exceeded to achieve this benefit. Clinical trial registration: As this study is not a clinical trial, no registration was required.

Gene regulation and signaling transduction in mediating the self-renewal, differentiation, and apoptosis of spermatogonial stem cells.

Infertility has become one of the most serious diseases worldwide, and 50% of this disease can be attributed to male-related factors. Spermatogenesis, by definition, is a complex process by which spermatogonial stem cells (SSCs) self-renew to maintain stem cell population within the testes and differentiate into mature spermatids. It is of great significance to uncover gene regulation and signaling pathways that are involved in the fate determinations of SSCs with aims to better understand molecular mechanisms underlying human spermatogenesis and identify novel targets for gene therapy of male infertility. Significant achievement has recently been made in demonstrating the signaling molecules and pathways mediating the fate decisions of mammalian SSCs. In this review, we address key gene regulation and crucial signaling transduction pathways in controlling the self-renewal, differentiation, and apoptosis of SSCs, and we illustrate the networks of genes and signaling pathways in SSC fate determinations. We also highlight perspectives and future directions in SSC regulation by genes and their signaling pathways. This review could provide novel insights into the genetic regulation of normal and abnormal spermatogenesis and offer molecular targets to develop new approaches for gene therapy of male infertility.

Physical symptoms in prolonged grief disorder: a case report.

Prolonged grief disorder (PGD) was added as a new disorder to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) in 2022. PGD is defined as an intense yearning or longing for the deceased and preoccupation with thoughts or memories of the deceased. The official diagnostic criteria for PGD do not include physical symptoms, but it is sometimes associated with somatic symptoms. We present the case of a patient suffering from facsimile illness who lost her husband due to the deterioration of a brain tumor. She suffers from similar physical symptoms (severe headache reminiscent of a brain tumor, and hypertension) as her deceased husband. We focused on the dual process model in which grief exposure and behavioral activation began, ensuring an oscillation between loss-oriented grief (e.g., crying, feeling a continuing bond) and restoration-oriented grief (e.g., attending to life changes, new roles/identities/relationships). Outpatient psychotherapy based on the dual-process model of grief improved her physical symptoms. This case report highlights the physical symptoms experienced by those bereaved by a deceased loved one. Exposure therapy and behavioral activation approaches based on the dual-process model of grief response were effective in reducing the physical symptoms of facsimile illness. Physical symptoms in deceased family members triggered by bereavement are often overlooked and need to be recognized.

Benefit delayed immunosenescence by regulating CD4+T cells: A promising therapeutic target for aging-related diseases.

CD4+T cells play a notable role in immune protection at different stages of life. During aging, the interaction between the body's internal and external environment and CD4+T cells results in a series of changes in the CD4+T cells pool making it involved in immunosenescence. Many studies have extensively examined the subsets and functionality of CD4+T cells within the immune system, highlighted their pivotal role in disease pathogenesis, progression, and therapeutic interventions. However, the underlying mechanism of CD4+T cells senescence and its intricate association with diseases remains to be elucidated and comprehensively understood. By summarizing the immunosenescent progress and network of CD4+T cell subsets, we reveal the crucial role of CD4+T cells in the occurrence and development of age-related diseases. Furthermore, we provide new insights and theoretical foundations for diseases targeting CD4+T cell subsets aging as a treatment focus, offering novel approaches for therapy, especially in infections, cancers, autoimmune diseases, and other diseases in the elderly.