Oncologic Disorders Research Articles

PROTAC Beyond Cancer- Exploring the New Therapeutic Potential of Proteolysis Targeting Chimeras.

In the realm of oncology, the transformative impact of PROTAC (PROteolysis TAgeting Chimeras) technology has been particularly pronounced since its introduction in the 21st century. Initially conceived for cancer treatment, PROTACs have evolved beyond their primary scope, attracting increasing interest in addressing a diverse array of medical conditions. This expanded focus includes not only oncological disorders but also viral infections, bacterial ailments, immune dysregulation, neurodegenerative conditions, and metabolic disorders. This comprehensive review explores the broadening landscape of PROTAC application, highlighting ongoing developments and innovations aimed at deploying these molecules across a spectrum of diseases. Careful consideration of the design challenges associated with PROTACs reveals that, when appropriately addressed, these compounds present significant advantages over traditional therapeutic approaches, positioning them as promising alternatives. To evaluate the efficacy of PROTAC molecules, a diverse array of assays is employed, ranging from High-Throughput Imaging (HTI) assays to Cell Painting assays, CRBN engagement assays, Fluorescence Polarization assays, amplified luminescent proximity homogeneous assays, Timeresolved fluorescence energy transfer assays, and Isothermal Titration Calorimetry assays. These assessments collectively contribute to a nuanced understanding of PROTAC performance. Looking ahead, the trajectory of PROTAC technology suggests its potential recognition as a versatile therapeutic strategy for an expansive range of medical conditions. Ongoing progress in this field sets the stage for PROTACs to emerge as valuable tools in the multifaceted landscape of medical treatments.

The development of growth hormone-releasing hormone analogs: Therapeutic advances in cancer, regenerative medicine, and metabolic disorders.

Growth Hormone-Releasing Hormone (GHRH) and its analogs have gained significant attention for their therapeutic potential across various domains, including oncology, regenerative medicine, and metabolic disorders. Originally recognized for its role in regulating growth hormone (GH) secretion, GHRH has since been discovered to exert broader physiological effects beyond the pituitary gland, with GHRH receptors identified in multiple extrahypothalamic tissues, including tumor cells. This review explores the development of both GHRH agonists and antagonists, focusing on their mechanisms of action, therapeutic applications, and future potential. GHRH agonists have shown promise in promoting tissue regeneration, improving cardiac function, and enhancing islet survival in diabetes. Meanwhile, GHRH antagonists, particularly those in the MIA and AVR series, demonstrate potent antitumor activity by inhibiting cancer cell proliferation and downregulating growth factor pathways, while also exhibiting anti-inflammatory properties. Preclinical studies in models of lung, prostate, breast, and gastrointestinal cancers indicate that GHRH analogs could offer a novel therapeutic approach with minimal toxicity. Additionally, GHRH antagonists are being investigated for their potential in treating neurodegenerative diseases and inflammatory conditions. This review highlights the versatility of GHRH analogs as a promising class of therapeutic agents, poised to impact multiple fields of medicine.

Literature review, surgical decision making algorithm, and AGREE II-S comparison of national and international recommendations and guidelines in pelvic organ prolapse surgery.

The average lifespan has increased over time due to improvements in quality of life, leading to an aging population that stays healthy for longer. Pelvic organ prolapse (POP), whether uterine or vaginal, is a problem that severely impairs quality of life and imposes significant restrictions. The present study provides the reader with a summary of the many surgical techniques used in POP surgery, comparing international guidelines, offering an algorithm that is simple to understand, and allows the reader to quickly choose the table that includes the best surgical therapy for each individual. Using relevant keywords, the writers searched the PubMed and Scopus databases for relevant publications from 2000 to April 2023. Studies with cases of oncologic disorders or prior hysterectomy performed for another reason were not included in the analysis. Ten distinct international guidelines are highlighted and examined in the present study. We used the Appraisal of Guidelines for Research and Evaluation II-S (AGREE II-S) method to assess their quality, and incorporated the results into the conclusion. Worldwide, anterior colporrhaphy is the preferred method of treating anterior compartment abnormalities, and mesh is virtually always used when recurrence occurs (which happens in about half of the cases). Worldwide, posterior colporrhaphy is commonly used to repair posterior compartment abnormalities. Only a few national guidelines (the Iranian guideline, Acta Obstetricia et Gynecologica Scandinavica [AOGS], and the German-speaking countries) permit the use of mesh or xenograft in cases of recurrence. There is agreement on the abdominal approach (sacrocolpopexy) with mesh for treating apical deformities. Sacrospinous-hysteropexy is the standard method used to guide the vaginal approach; mesh is typically used to aid in this process. There are just three recommendations that do not include vaginal operations: HSE, AOGS, and Iran. Of obliteration techniques, colpocleisis is unquestionably the best. In conclusion, our analysis highlights the significance of customized methods in POP surgery, taking into account the requirements and preferences of each patient. To choose the best surgical therapy, criteria and patient features must be carefully considered.

Diagnostic accuracy of imaging modalities for detection of spinal metastases: a systematic review and meta-analysis.

Detecting spinal metastases is highly relevant in patients with oncological disorders as it can affect the staging and treatment of their disease. We aimed to evaluate the diagnostic performance of computed tomography (CT), magnetic resonance imaging (MRI), FDG positron emission tomography (PET)/CT, bone scintigraphy (BS), and single-photon emission computed tomography (SPECT) for spinal metastases detection. Medline, EMBASE, and Web of Science were systematically searched until March 2024 for diagnostic accuracy studies on spinal metastases detection (PROSPERO-registration: CRD42024540139). Data extraction and quality assessment using the QUADAS-2 tool were performed by two independent reviewers. Using bivariate random effects modeling, pooled sensitivities, specificities, and diagnostic odds ratios (DOR) were calculated, and hierarchical summary operating curves were constructed. Twenty-five studies (49 datasets), encompassing 3102 patients were included. Per-patient pooled sensitivities of CT, MRI, PET/CT, BS and SPECT were 70%, 93%, 82%, 75%, and 84%, respectively. Pooled specificities were 74%, 85%, 75%, 92%, and 81%, respectively. Per-lesion pooled sensitivities of CT, MRI, PET/CT, BS and SPECT were 76%, 91%, 92%, 77%, and 92%, respectively. Pooled specificities were 91%, 94%, 85%, 52%, and 86%, respectively. MRI had the highest DOR in per patient and lesion analyses. MRI had highest diagnostic accuracy for spinal metastases detection on patient and lesion level, suggesting a broader use in addition to the routine staging CT, at least in patients at high risk and where the detection of a spinal metastasis could alter therapy decisions. Herein, results should be considered with the limitations of each modality.

Prevalence of tinnitus in temporomandibular joints disorder patients

BackgroundDisorders affecting the temporomandibular joint (TMJ), related structures, and the masticatory muscles are called temporomandibular disorders (TMD). The two most typical symptoms are mouth opening restriction and pain. Costen noted the connection between TMD and tinnitus in 1934. These conditions are brought about by the shared structures that connect the TMJ and the auditory apparatus (bones and muscles) through a shared innervation source and specific ligaments. Wright addresses Costen ideas, which suggest that otological symptoms of TMD could be caused by auriculotemporal nerve damage, Eustachian tube restriction, or other factors causing an incorrect intratympanic pressure adjustment.MethodsCross-sectional observation was regulated at Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Cairo University. The following are the inclusion criteria: patients with a TMD diagnosis and those older than 16 years old. The following conditions are excluded: neurological or oncological disorders, ear infection, and a history of face trauma.ResultsThe total number was 196 patients, 63.8% females and 36.2% males. A total of 76.5% had bilateral joint pain, and 21.9% had unilateral joint pain. While 70.4% had bilateral muscle pain, 18.9% had unilateral muscle pain. A total of 91.8% had mild tinnitus, while 8.2% had moderate tinnitus.ConclusionIn this study, 8.2% of patients complaining of tinnitus had severe tinnitus, while 91.8% had mild tinnitus.

Carcinoembryonic antigen-related cell adhesion molecule 1 in cancer: Blessing or curse?

The Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, also CD66a), a transmembrane glycoprotein of the immunoglobulin superfamily, is a pivotal mediator of various physiological and pathological processes, including oncologic disorders. However, its precise role in tumorigenicity is contradictory discussed by several clinical studies. This review aims to elucidate the clinical significance of CEACAM1 in different cancer entities focusing on tumour formation, progression and metastasis as well as on CEACAM1-mediated treatment resistance. Furthermore, we discuss the contribution of CEACAM1 to cancer immunity and modulation of the inflammatory microenvironment and finally provide a comprehensive review of treatment regimens targeting this molecule.

Development of a quantitative prediction algorithm for human cord blood-derived CD34+ hematopoietic stem-progenitor cells using parametric and non-parametric machine learning models

The transplantation of CD34+ hematopoietic stem-progenitor cells (HSPCs) derived from cord blood serves as the standard treatment for selected hematological, oncological, metabolic, and immunodeficiency disorders, of which the dose is pivotal to the clinical outcome. Based on numerous maternal and neonatal parameters, we evaluated the predictive power of mathematical pipelines to the proportion of CD34+ cells in the final cryopreserved cord blood product adopting both parametric and non-parametric algorithms. Twenty-four predictor variables associated with the cord blood processing of 802 processed cord blood units randomly sampled in 2020–2022 were retrieved and analyzed. Prediction models were developed by adopting the parametric (multivariate linear regression) and non-parametric (random forest and back propagation neural network) statistical models to investigate the data patterns for determining the single outcome (i.e., the proportion of CD34+ cells). The multivariate linear regression model produced the lowest root-mean-square deviation (0.0982). However, the model created by the back propagation neural network produced the highest median absolute deviation (0.0689) and predictive power (56.99%) in comparison to the random forest and multivariate linear regression. The predictive model depending on a combination of continuous and discrete maternal with neonatal parameters associated with cord blood processing can predict the CD34+ dose in the final product for clinical utilization. The back propagation neural network algorithm produces a model with the highest predictive power which can be widely applied to assisting cell banks for optimal cord blood unit selection to ensure the highest chance of transplantation success.

Recent development of nanomaterials-based PDT to improve immunogenic cell death.

Photodynamic therapy (PDT) is a clinically approved therapeutic modality for treating oncological and non-oncological disorders. PDT has proclaimed multiple benefits over further traditional cancer therapies including its minimal systemic toxicity and selective ability to eliminate irradiated tumors. In PDT, a photosensitizing substance localizes in tumor tissues and becomes active when exposed to a particular wavelength of laser light. This produces reactive oxygen species (ROS), which induce neoplastic cells to die and lead to the regression of tumors. The contributions of ROS to PDT-induced tumor destruction are described by three basic processes including direct or indirect cell death, vascular destruction,and immunogenic cell death. However, the efficiency of PDT is significantly limited by the inherent nature and tumor microenvironment. Combining immunotherapy with PDT has recently been shown to improve tumor immunogenicity while decreasing immunoregulatory repression, thereby gently modifying the anticancer immune response with long-term immunological memory effects. This review highlights the fundamental ideas, essential elements, and mechanisms of PDT as well as nanomaterial-based PDT to boost tumor immunogenicity. Moreover, the synergistic use of immunotherapy in combination with PDT to enhance immune responses against tumors is emphasized.

Precision Medicine: Utilizing Genomic Insights for Customized Therapeutic Strategies

Precision medicine represents a revolutionary shift in healthcare by utilizing genomic insights to develop customized therapeutic strategies tailored to an individual’s genetic makeup. This article explores the integration of genomic data into personalized treatment plans, focusing on how advances in genetic sequencing and bioinformatics are enabling more targeted and effective medical interventions. By analyzing a patient’s genome, precision medicine allows for more accurate diagnosis, prediction of disease risk, and optimization of treatment options, particularly in fields such as oncology, cardiology, and rare genetic disorders. The study highlights key advancements in pharmacogenomics, which plays a critical role in determining how individuals respond to specific drugs based on their genetic profiles. Case studies in cancer treatment illustrate the success of precision therapies like targeted gene therapy and immunotherapy, which have significantly improved patient outcomes. Despite these advancements, challenges such as the high cost of genomic sequencing, ethical considerations, and the need for standardized clinical guidelines remain barriers to widespread adoption. The article concludes by emphasizing the potential of precision medicine to transform healthcare by shifting from a one-size-fits-all model to a more individualized and efficient approach to disease management.

Genetic polymorphism in untranslated regions of PRKCZ influences mRNA structure, stability and binding sites

BackgroundVariations in untranslated regions (UTR) alter regulatory pathways impacting phenotype, disease onset, and course of disease. Protein kinase C Zeta (PRKCZ), a serine-threonine kinase, is implicated in cardiovascular, neurological and oncological disorders. Due to limited research on PRKCZ, this study aimed to investigate the impact of UTR genetic variants’ on binding sites for transcription factors and miRNA. RNA secondary structure, eQTLs, and variation tolerance analysis were also part of the study.MethodsThe data related to PRKCZ gene variants was downloaded from the Ensembl genome browser, COSMIC and gnomAD. The RegulomeDB database was used to assess the functional impact of 5’ UTR and 3’UTR variants. The analysis of the transcription binding sites (TFBS) was done through the Alibaba tool, and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) was employed to identify pathways associated with PRKCZ. To predict the effect of variants on microRNA binding sites, PolymiRTS was utilized for 3’ UTR variants, and the SNPinfo tool was used for 5’ UTR variants.ResultsThe results obtained indicated that a total of 24 variants present in the 3’ UTR and 25 variants present in the 5’ UTR were most detrimental. TFBS analysis revealed that 5’ UTR variants added YY1, repressor, and Oct1, whereas 3’ UTR variants added AP-2alpha, AhR, Da, GR, and USF binding sites. The study predicted TFs that influenced PRKCZ expression. RNA secondary structure analysis showed that eight 5’ UTR and six 3’ UTR altered the RNA structure by either removal or addition of the stem-loop. The microRNA binding site analysis highlighted that seven 3’ UTR and one 5’ UTR variant altered the conserved site and also created new binding sites. eQTLs analysis showed that one variant was associated with PRKCZ expression in the lung and thyroid. The variation tolerance analysis revealed that PRKCZ was an intolerant gene.ConclusionThis study laid the groundwork for future studies aimed at targeting PRKCZ as a therapeutic target.

Systemic immune-inflammatory markers and long-term prognosis after revascularization in Moyamoya disease: a retrospective study.

Systemic immune-inflammatory markers combine various individual inflammatory cell parameters to comprehensively explore their relationship with the development and long-term outcomes of cardiovascular, cerebrovascular, and oncological disorders. The systemic immune-inflammatory marker index has not been extensively studied in terms of its impact on the long-term prognosis following cerebral revascularization in MMD patients. Our research aims to address this gap and improve the prediction of long-term outcomes for these patients. We included 851 patients with Moyamoya disease who underwent cerebral revascularization at our medical center from 2009 to 2021. Systemic immune-inflammatory markers were calculated based on routine blood test results at admission, and follow-up was conducted for over 6 months after surgery. During monitoring and upon release, we evaluated patient neurological condition by utilizing the modified Rankin Scale (mRS). We examined the correlation between alterations in mRS ratings and systemic immune-inflammatory markers. Comparing the unfavorable long-term prognosis group to the favorable long-term prognosis group, it was found that the NLR level was markedly higher (p = 0.037), while the LMR was lower in the unfavorable long-term prognosis group (p = 0.004). Results from logistic regression analysis revealed that the high-level LMR group had a lower risk of unfavorable long-term prognosis compared to the low-level group (T3: OR = 0.433, 95% CI [0.204-0.859], p = 0.026). The AUC of the model was 0.750 (95% CI [0.693-0.806]). Lymphocyte-to-monocyte ratio levels are independently linked to an increased risk of unfavorable long-term prognosis, highlighting LMR as a new and effective predictor for postoperative Moyamoya patients.

Recent Progress and Perspectives in Sodium-Glucose Co-transporter 1/2 Inhibitors.

Sodium-Glucose Co-transporter-1/2 (SGLT1/2) inhibitors (also called glifozins) are a class of glucose-decreasing drugs in adults with Type 2 Diabetes (T2D). SGLT2 inhibitors diminish sodium and glucose reabsorption in the renal proximal convoluted tubule. Recent clinical trials have revealed that SGLT2 inhibitors might be beneficial for treating diseases other than diabetes, including chronic renal disease and Heart Failure (HF). Currently, SGLT2 inhibitors are recommended not only for the glycemic management of T2D but also for cardiovascular protection. SGLT2 inhibitors have become one of the foundational drugs for HF with reduced Ejection Fraction (HFrEF) treatment and the first medications with proven prognostic benefit in HF with preserved Ejection Fraction (HFpEF). At present, 11 SGLT1/2 inhibitors have been approved for clinical use in different countries. Beyond their anti-hyperglycemic effect, these inhibitors have shown clear cardio- and nephroprotective properties. A growing body of research studies suggests that SGLT1/2 inhibitors may provide potential clinical benefits in metabolic as well as oncological, hematological, and neurological disorders.

Expression of Growth Hormone-Releasing Hormone and Its Receptor Splice Variants in a Cohort of Hungarian Pediatric Patients with Hematological and Oncological Disorders: A Pilot Study.

Hematological and oncological diseases are still among the leading causes of childhood mortality. Expression of growth hormone-releasing hormone (GHRH) and its receptors (GHRH-R) has been previously demonstrated in various human tumors, but very limited findings are available about the presence and potential function of GHRH-Rs in oncological and hematological disorders of children. In this study, we aimed to investigate the expression of mRNA for GHRH and splice variant 1 (SV) of GHRH-R in 15 pediatric hematological/oncological specimens by RT-PCR. The presence and binding characteristics of GHRH-R protein were also studied by Western blot and ligand competition assays. Of the fifteen specimens studied, eleven pediatric samples (73%) showed the expression of mRNA for GHRH. These eleven samples also expressed mRNA for GHRH receptor SV1. GHRH-R protein was found to be expressed in two benign tumor samples and five malignant tumors examined by Western blot. The presence of specific, high affinity binding sites on GHRH-R was demonstrated in all of the seven human pediatric solid tumor samples investigated. Our results show that the expression of GHRH and SV1 of GHRH-R in hemato-oncological diseases in children can pave the way for further investigation of GHRH-Rs as potential molecular targets for diagnosis and therapy.

Nutritional disorders and survival rate of elderly and geriatric patients with CKD 3B-5 stage

BACKGROUND. The prevalence of CKD in the population of the elderly and geriatric patients is varies from 23.4% to 35.8%. Nutritional status was recognized as an important factor of CKD prognosis. One of the factors affecting their survival is nutritional status. There have not been many studies on the effect of eating disorders on the survival of elderly and senile patients with CKD.THE AIM: to assess the impact of nutritional status on the survival of elderly patients with CKD stages 3b-5.PATIENTS AND METHODS. We’ve studied 190 people with CKD stages 3b-5 (eGFR<45 ml/min/m2) with an average age of 76 [67;86]. Exclusion criteria’s: dialysis, acute cardiovascular disorders, oncology, and psychiatric disorders. Nutritional status was assessed by Subjective Global Assessment scale, the 5-year risk of the death was evaluated absolute by the Bansal scale. The duration of study - 36 month.RESULTS. In the group of elderly and geriatric patients with CKD stages 3b-5, normal nutritional status was determined in 40.1% of patients, mild to moderate malnutrition in 54.7%, and protein-energy wasting (PEW) in 5.2%; up to 2.8% of patients were underweight. The best 3-year survival rate was observed in patients with normal nutritional status, mild nutritional status disorders and obesity, the worst survival rate - in patients with PEW and underweight (p<0,001). In the group of patients with CKD stage 4 the average Bansal score scale was 8 points, which corresponds to 69% of the absolute risk of death within 5 years; in patients with CKD stage 5, the average score was also 8 [7, 8]. CONCLUSION. In the group of elderly and geriatric patients with CKD stage 3b-5 and PEW survival rate was significantly lower than in patients without nutritional disorders and mild nutritional disorders; we didn’t find correlation between the estimated absolute risk of death according to the Bansal scale and actual survival in 3-year observation period.

The Palliative Care in Patients with Oncological Diseases - a New Medical and Therapeutic Approach

The life epectancy increase in patients with cancer requires more attention to the quality of life and mental health status of this population. The aim of the current research is to change the perspective on the evolution of oncological disorders, regardless of their localization, stage, or complications, in terms of survival chances, by eploring the essential role of psychiatric medication on the core physical and mental health-related outcomes. This is a prospective, naturalistic study, that enrolled 284 oncological patients, distributed in three groups, diagnosed with lung cancer, metastatic lung cancer or other types of cancer, who received psychotropic medication for their mood symptoms, and changes in the primary outcomes (i.e., patients’ mood and pain, and quality of the mental status of the caregivers) were monitored for si months. The results reflected the efficacy of psychopharmacological intervention initiated early after the diagnosis of cancer was formulated, according to the scores on the Integrated Palliative Care Outcome Scale (IPOS). The severity of pain, the intensity of depression, and aniety in family members decreased significantly during si months of the standard-of-care psychotropic medication administered for depressive disorders. In the long term, the objective is to change the oncological protocols to accommodate an early introduction of psychiatric medication in the evolution of oncological disease, even in the contet of moderate physical symptoms with uncertain etiology, which causes a deterioration in overall functionality and quality of life. A new notion, created by the first author, is supported by this research, i.e., “long-term oncological survivorship care,” which will replace the former concept of palliative care, which refers to “end-of-life care,” or “comfort care,” in relation to the oncological contet.

#2108 Secondary amyloidosis in a cancer patient on pembrolizumab—an unusual finding

Abstract Background and Aims With the widening horizon of ICPIs in the management of oncological disorders, we require to remain vigilant of the possible iRAEs. We present a case report of secondary amyloidosis in at metastatic non-small cell lung carcinoma (NSCLC) patient treated with Pembrolizumab. We aim to describe the clinic-biological & histopathological characteristics of ICPI-related kidney injury which may be beyond interstitial nephritis & its response to treatment & the role of kidney biopsy to define ICPI-related kidney injury. Treatment is challenging due to a paucity of relevant data, implicating further studies. Treatment with colchicine and steroids, tocilizumab in the setting of elevated interleukin-6 (IL6) levels have been reported in case series; unfortunately no appreciable renal benefit were noted. Method 77 year male, diabetic & hypertensive on regular medication for >15 yr, reformed smoker (≈50 pack-years of cigarette) diagnosed with NSCLC (EGFR–wild type, PDL1–70%), received Pembrolizumab (13 cycles) & Paclitaxel + Carboplatin & was in remission. Follow up PET showed partial response—new lesions in brain. Gemcitabine added to the treatment & had received 2 cycles, till hospitalization with febrile episode, decreased oral intake & progressive edema. Clinical evaluation was non-contributory. Hematology & biochemical evaluation (Table 1) showed raised serum creatinine 1.1 mg/dL (baseline 1 mg/dL), urinalysis—2+ protein, quantification showed 2.9295 g/24 h → 6.38 g/24 h (baseline uPCR-0.19 g/g). Abdominal ultrasound & ECHO finding were not conclusive. Fundoscopy showed no evidence of proliferative diabetic or hypertensive retinopathy. Results Kidney Biopsy (Figure) was done. LM showed, few of 8 gloms with mild segmental mesangial expansion due to amorphous extracellular deposits which was PAS & silver negative but showed congophilia (Fig. A,B,C,D). If negative for albumin, IgG, IgA, C3, C1q & had 1+ granularity in the mesangium on IgM staining & showed no light chain restriction in glomeruli & tubular cast for kappa & lambda. IHC (Fig. E) was positive for serum amyloid associated proteins. EM revealed minimal subendothelial & mesangial expansion due to extracellular material organized into randomly arranged fine fibrils, & no significant foot process effacement, electron dense deposits along the capillary basement membrane or within mesangium, glomerular basement membrane, thereby excluding possibility of light chain deposition disease. Conclusion Secondary amyloidosis with ICPI use has uncommonly & with Pembrolizumab rarely been reported. Treatment is challenging due to paucity of literature. Hassan Izzedine et al. in their case series, on Pembrolizumab treated cancer patient [N = 676], showed 12 patients (7 men) (Incidence 1.77%) developed AKI (n = 10) &/or Proteinuria (n = 2), median duration of use 9 months. All (n = 12) underwent renal biopsy, which showed AIN in 4, ATI in 5, MCD in 2. Recovery happened with withdrawal of drug coupled with corticosteroid. Reintroduction resulted in more severe recurrence of AIN in 1 patient only. Lapman et al. reported 1 case of secondary amyloidosis in cancer patients treated with Pembrolizumab. 42yr male Caucasian, had no reported chronic illness, except Asthma. Similarly developed significant proteinuria (Urine Pro 3+) & AKI (Sr. Creat 1.58 mg/dl; Baseline 1.0 mg/dl) after 90 days of Pembrolizumab therapy. Under went 2 Kidney Biopsy–1st Biopsy revealed AA amyloid. AA amyloidosis was attributed to Pembrolizumab as repeat Bx revealed progressive deposits despite remission of malignancy, but his kidney disease progressed, and had to be initiation on maintenance hemodialysis. Stopping Pembrolizumab & corticosteroids led to resolution of proteinuria in our patient too.

Efficacy of long-term albumin therapy in the treatment of decompensated cirrhosis.

Decompensated liver cirrhosis has a poor prognosis, with a median overall survival of two to four years, which is worse than for many oncological disorders. These patients are highly susceptible to infections due to increased systemic inflammation leading to kidney failure and death. The aim was to study the efficacy of albumin in reducing episodes of decompensation, preventing bacterial infection, kidney dysfunction and mortality. Study involved patients with Child B or C cirrhosis with an albumin level below 3.0g/dL, who were administered 20% human albumin weekly with standard medical treatment (SMT) for threemonths or till serum albumin levels were 4.0g/dL (whichever is earlier) and compared with age and sex-matched controls who received only SMT. The primary end-point was six-month mortality and the secondary end-points were reduction in infections, kidney dysfunction, ascites recurrence, hepatic encephalopathy (HE), gastrointestinal (GI) bleed and complications of cirrhosis. From September 2021 to January 2023, 88 cases and 86 controls were taken and followed up for sixmonths. Overall, six-month survival was not statistically significant between groups (95.1% vs. 91.9%; p = 0·330). The incidence of recurrence of ascites (34.09% vs. 59.3%, p < 0.001), kidney dysfunction (6.8% vs. 24.4%, p < 0.001), HE (15.9% vs, 37.2%, p = 0.015), spontaneous bacterial peritonitis(SBP) (3.4% vs 17.4%, p = 0.002) and non-SBP infections (7.9% vs. 18.6%, p = 0.038) were significantly less in cases as compared with controls; however, GI bleed (14.8% vs. 17.4%, p = 0.632) was not statistically significant. Long-term human albumin acts as a disease-modifying treatment in patients with decompensated cirrhosis.

In silico screening of potential agonists of a glucagon-like peptide-1 receptor among female sex hormone derivatives

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that exerts its pleiotropic effects through a specific GLP-1 receptor (GLP-1R). The hormone–receptor complex might regulate glucose-dependent insulin secretion, and energy homeostasis; moreover, it could decrease inflammation and provide cardio- and neuroprotection. Additionally, the beneficial influence of GLP-1 on obesity in women might lead to improvement of their ovarian function. The links between metabolism and reproduction are tightly connected, and it is not surprising that different estrogen derivatives, estrogen-receptor modulator (SERM) and progestins used for gonadal and oncological disorders might influence carbohydrate and lipid metabolism. However, their possible influence on the GLP-1R has not been studied. The docking scores and top-ranked poses of raloxifene were much higher than those observed for other investigated SERMs and estradiol per se. Among different studied progestins, drospirenone showed slightly higher affinity to GLP-1R. Herein, the same data set of the drugs is evaluated by molecular dynamics (MD) simulations and compared with the obtained docking result. Notably, it is demonstrated that the used docking protocol and the applied MD calculations ranked the same ligand (raloxifene) as the best one. In the present study, raloxifene might exert an allosteric influence on GLP-1R signaling, which might contribute to potential beneficial effects on metabolism and weight regulation. However, further experimental and clinical studies are needed to reveal if the GLP-1R modulation has a real biological impact. Communicated by Ramaswamy H. Sarma

Role of Mitochondrial Dysfunction in Related Diseases-A Review

Background: Mitochondrial dysfunction (MD) is increasingly recognized for its role in a wide array of diseases, extending beyond primary mitochondrial diseases (PMDs) to include secondary mitochondrial diseases (SMDs) and a broad spectrum of neurodegenerative, cardiovascular, metabolic, and oncological disorders. This growing awareness underscores the need for a comprehensive review of the mechanisms underlying MD, its clinical implications, and emerging therapeutic strategies. Objective: To synthesize current knowledge on the pathogenesis of diseases associated with MD, delineate the distinction between PMDs and SMDs, explore the genetic and environmental factors contributing to MD, and assess the potential of novel therapeutic approaches targeting mitochondrial dysfunction. Methods: A narrative review was conducted through a structured search of PubMed, Scopus, Web of Science, and Google Scholar, focusing on articles published up to April 2023. Keywords related to mitochondrial dysfunction and its implications across various diseases were used to identify relevant studies. Inclusion criteria targeted original research, reviews, and meta-analyses published in English that contributed to understanding MD's role in disease pathogenesis and treatment. Data extraction and synthesis were performed to highlight key findings, mechanisms, and therapeutic strategies. Results: The review emphasizes the critical role of mitochondrial dysfunction in the pathogenesis of a wide range of diseases. It identifies specific mtDNA mutations contributing to PMDs and highlights how SMDs arise from mitochondrial impairment secondary to other conditions. The synthesis of findings points to oxidative stress, impaired ATP production, and altered mitochondrial dynamics as central to MD's impact on cellular and systemic health. Additionally, the review explores emerging therapies, including mitochondrial-targeted antioxidants, gene therapy, and metabolic interventions, underscoring their potential in managing MD-related diseases. Conclusion: Mitochondrial dysfunction is a pivotal factor in the etiology of numerous diseases, with genetic mutations and environmental influences contributing to its development and progression. Understanding these complex mechanisms is essential for devising effective therapeutic interventions. While significant advances have been made, further research is needed to fully exploit the therapeutic potential of targeting mitochondrial dysfunction.

Randomised trials conducted using cohorts: a scoping review

IntroductionCohort studies generate and collect longitudinal data for a variety of research purposes. Randomised controlled trials (RCTs) increasingly use cohort studies as data infrastructures to help identify and recruit trial...