Abstract:

Follicular lymphoma (FL) is the second most common form of non-Hodgkin’s lymphoma (NHL) and accounts for about 5% of all hematological malignancies. Despite therapeutic advances, FL follicular lymphoma remains an incurable disease, with frequent relapses and increasingly shorter disease control intervals. Bispecific antibodies (bsAbs) are molecules that target two different epitopes or antigens. The mechanism of action is determined by the molecular targets and structure of the bsAbs. Several bsAbs have already changed the therapeutic landscape of hematological malignancies and some solid tumors. In particular, in this article we review the general principles on follicular lymphoma and established and innovative therapies including bsAbs, in particular the bsAb mosunetuzumab, a new bispecific antibody that acts on CD3 epitopes of T lymphocytes and CD20 epitopes of B lymphocytes with the aim of inducing T lymphocyte-mediated elimination of malignant B lymphocytes, its safety and efficacy with the analysis of no. 3 patients who completed treatment with the drug mosunetuzumab in the A.O. Pia Fondazione di Culto e Religione ‘Card. G. Panico’, Tricase (Lecce).

Abstract: BACKGROUND In Kenya, end-stage renal disease is a significant public health burden treated primarily with hemodialysis in county hospitals, yet comprehensive outcome data from these routine settings are scarce. AIM To evaluate one-year clinical outcomes and identify independent predictors of mortality among ESRD patients undergoing hemodialysis at a Kenyan county hospital. METHODS We conducted a retrospective cohort study of all patients who initiated hemodialysis for ESRD at Murang'a County Referral Hospital between January 2024 and January 2025. Data on demographics, clinical characteristics, comorbidities, and treatment parameters were extracted from hospital electronic medical records and dialysis unit records. Cox proportional hazards regression was used to identify factors associated with one-year mortality. RESULTS Of 79 patients analysed (median age 62.0 years, IQR 48.0-74.0; 65.8% male), the one-year all-cause mortality rate was 34.2% (27/79). The cohort demonstrated a heavy reliance on central venous catheters (89.9%, 71/79) rather than arteriovenous fistulas (10.1%, 8/79). 3 Non-survivors were significantly older (median 73.0 vs 58.0 years, p<0.001) and had lower baseline haemoglobin (7.1 vs 8.6 g/dL, p=0.008). In multivariable analysis, older age (aHR 1.05 per year, 95% CI 1.01-1.09, p=0.012) and central venous catheter use (aHR 3.12, 95% CI 1.08-9.01, p=0.036) remained independent predictors of mortality. Lower eGFR and hemoglobin were significant in univariate analysis but not in the adjusted model. Comorbidities, including HIV and diabetes, did not reach statistical significance. CONCLUSION This study found high one-year mortality in Kenyan hemodialysis patients, with older age and catheter use showing strong associations with death. The near-universal use of CVCs is a marker of systemic challenges in pre-dialysis care, underscoring the urgent need for vascular access programs and improved care strategies to improve survival.

Abstract: α-Mangostin, a natural product from Garcinia mangostana L, presents most antibacterial activity in plant flavonoids against Staphylococcus aureus so far. Recently, it was reported that the quinone pool is a key target of α-mangostin against Gram-positive bacteria. To further confirm this and investigate the detail of α-mangostin killing S. aureus, the interactions between α-mangostin and a key enzyme as type II NADH:quinone oxidoreductase (NDH-2), together with possible non-enzymatic mechanisms, were explored. Through the enzyme kinetic inhibition experiments, it was found that α-mangostin mainly competes with the menaquinone-binding sites of NDH-2, and the half-maximal inhibitory concentration (IC₅₀) of α-mangostin on NDH-2 is 4.95 μM. Fluorescence analyses indicated that α-mangostin can spontaneously bind to NDH-2 to form an α-mangostin–NDH-2 complex. Subsequently, molecular simulation further indicated that α-mangostin can dock to the menaquinone-binding sites of NDH-2. Another, non-enzymatic mechanism showed that α-mangostin can cause membrane potential depolarization and disrupt the proton motive force balance, thereby promoting the cell-membrane destruction of S. aureus. These results suggest that α-mangostin mainly can interact with the amino acid residues at the menaquinone-binding pocket of NDH-2 to block the electron transfer at the quinone pool in the respiratory chain of S. aureus, and which will hinder the energy supply and promote its incidental effect on membrane disruption, ultimately leading to the death of S. aureus. This once again proves that the quinone pool is a key target of plant flavonoids against Gram-positive bacteria.

Abstract: The compelling study by Liu et al delivers a critical verdict: The primary tumor site is not merely an anatomical detail, but a fundamental prognostic imperative in the surgical management of colorectal liver metastases. Their analysis of 178 patients definitively establishes right-sided colonic origin as an independent harbinger of aggressive disease, characterized by significantly higher recurrence rates and inferior survival outcomes compared to left-sided and rectal cancers. This biological dichotomy is further elucidated by the strong association of right-sided tumors with an adverse prognostic profile, including rampant lymph node metastasis, elevated D-dimer (reflecting a pro-thrombotic, pro-metastatic state), hypoalbuminemia, and resistance to neoadjuvant therapy. These findings necessitate an immediate paradigm shift in clinical practice. We can no longer treat colorectal cancer as a monolith. Preoperative risk stratification, surgical decision-making, and adjuvant therapy plans must be tailored according to the primary tumor location. For patients with right-sided primaries, these data suggest a more aggressive multimodal approach and vigilant, personalized surveillance to improve upon the discouraging outcomes this study clearly exposes.

Abstract: Background: The management of asymptomatic cryptococcal antigenemia in pregnant women with advanced human immunodeficiency virus (HIV) disease presents a therapeutic dilemma. Clinicians must balance the risks of vertical transmission, immune reconstitution inflammatory syndrome (IRIS), and antifungal teratogenicity. Case Summary: We report a case of a 28-year-old HIV-positive woman in Kenya who presented at 34 weeks of gestation with symptoms suggestive of meningitis. She had self-discontinued her antiretroviral therapy (ART) 18 months prior. Laboratory investigations confirmed a positive serum cryptococcal antigen (CrAg) with a high HIV viral load (41200 copies/mL). Lumbar puncture ruled out meningeal involvement. A multidisciplinary team initiated preemptive therapy with high-dose fluconazole (800 mg daily). Faced with her advanced gestation and the imperative to prevent perinatal transmission, a calculated risk was taken to initiate ART (tenofovir/lamivudine/dolutegravir) after only 7 days, a significant deviation from standard guidelines. At 36 weeks, she had a spontaneous vaginal delivery complicated by uterine inversion and postpartum hemorrhage, which was managed successfully. She did not develop cryptococcal IRIS. At 3-month follow-up, her viral load was suppressed (51 copies/mL), and her infant was HIV-negative with normal development at 6 months. Conclusions: This case highlights the importance of routine CrAg screening in pregnant women with advanced HIV. Preemptive fluconazole in the third trimester is feasible. The timing of ART initiation may need individualization to prevent vertical transmission in late gestation, particularly in the context of isolated antigenemia, where the IRIS risk profile may differ from cryptococcal meningitis. These decisions require multidisciplinary input and close monitoring.

Abstract: Purpose: Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory condition often accompanied by various comorbidities that significantly affect patient outcomes. High resolution computed tomography has emerged as a valuable tool for diagnosing and managing COPD-related comorbidities. This study aims to explore the impact of chest CT imaging in identifying and characterizing comorbidities in COPD patients. Methods: The study was conducted on 99 patients with COPD, with an average age of 67,8 (37-88), 86% were men (85), and 14% were women (14). The patients underwent chest HRCT to identify the presence of comorbidities. Results: According to the GOLD classification, ABE type, 3% were type A, 27% were type B, and 69% were type E. The prevalence of comorbidities identified on chest HRCT was reported as 66% for coronary artery calcification (CAC), 83% for osteoporosis, 36% for pulmonary artery enlargement (PAE), 31% for emphysema, 19% for bronchiectasis, 17% for hiatal hernia, 14% for lung cancer, 12% pulmonary infections and 3% for interstitial abnormalities. In 4% there were no comorbidities, one comorbidity was found in 11%, two comorbidities in 17%, and three comorbidities and more in 68% of cases. Conclusion: Chest HRCT imaging serves as a valuable tool for identifying and assessing comorbidities in patients with COPD. Incorporating chest CT imaging into the routine evaluation of COPD patients can contribute to a more comprehensive understanding of their condition and lead to better clinical outcomes.

Abstract: Immunotherapy has transformed cancer management. Patients receiving immune checkpoint inhibitors frequently experience concurrent pain and sleep disturbances that affect quality of life, treatment adherence, and overall survival. Nursing interventions addressing both symptoms remain poorly defined. This scoping review searched the Scopus, ScienceDirect, PubMed, and CINAHL for updates from 2019 to 2025 following PRISMA-ScR guidelines; ten studies were included (randomized controlled trials, systematic reviews, and observational studies for all cancers since focusing on melanoma alone would not give enough results. Nurse-led interventions included education, physical therapies (massage, reflexology, acupressure), behavioral approaches, and digital platforms (telehealth, electronic patient-reported outcomes). The patients achieved moderate short-term pain reductions, significantly improved quality of life, enhanced treatment adherence, and reduced emergency department visits by up to 45%. However, only 2/10 studies used validated instruments to measure sleep quality, and none designed primary interventions specifically targeting sleep disturbances in patients receiving immunotherapy. Long-term sustainability of pain interventions was questionable, with most effects attenuating beyond eight weeks except for psycho-educational approaches. Future research should develop integrated, nurse-delivered interventions addressing pain and sleep as interconnected symptoms, with extended follow-up periods and enhanced accessibility across diverse healthcare settings. Validated instruments to measure sleep quality should be employed.

Abstract: Introduction: Sjogren’s is an autoimmune disease that affects several organs, especially the heart, and raises cardiovascular risk. Investigating associations of hemoglobin-to-RDW ratio (HRR), vitamin D status, and cardiac function could provide valuable insights and biomarkers regarding early cardiovascular risk in patients with SD. Method: This cross-sectional study involved 61 patients diagnosed with primary Sjogren’s syndrome (pSS) based on ACR/EULAR criteria. Data on demographics, hematological (Hb, RDW), echocardiography, and serum vitamin D levels were collected. Echocardiograms were conducted by trained cardiologists following established guidelines, while vitamin D levels were measured using ELISA, and statistical analyses, including univariate linear regression, were adjusted for confounders. were performed with SPSS in order to identify whether HRR tertiles were related to cardiac function and vitamin D status. Results: A study of 61 Sjogren’s disease patients (mean age 59.8 years, 89% female) revealed that patients with a lower hemoglobin-to-RDW ratio (HRR ≤0.98) had significantly higher pulmonary artery pressures (PAPs) and lower values for the TAPSE/PAPs ratio, contributing to poor right heart function. These associations were particularly strong in patients with insufficient levels of vitamin D (< 30 ng/mL), while differences in other echocardiographic parameters remained nonsignificant between HRR groups. Conclusion: These findings underscore the clinical value of HRR as a composite biomarker that reflects the interplay between anemia, inflammation, and cardiovascular health in Sjogren’s disease. They also suggest that vitamin D status may be an important therapeutic consideration to mitigate cardiopulmonary risks in this population.

Abstract: The evolution of non-invasive mechanical ventilation (NIV) from the iron lung of the 1950s to the use of sophisticated ventilators with mask apparatus has allowed for the optimal management of a wide range of respiratory disorders. NIV is now a mainstay in the management of acute, chronic and acute on chronic hypoxemic and hypercapnic respiratory failure from diverse etiologies. While NIV offers an effective approach to avoid invasive mechanical ventilation with its inherent risks of lung injury and sedation related harms; it is a complex modality that requires a nuanced approach to management [1]. As the use of NIV has become ubiquitous, complex challenges are faced in the initiation, management and discontinuation of the treatment. We review complex clinical scenarios that present during liberation from non-invasive mechanical ventilation and an approach to successful weaning and liberation in these patient populations.

Abstract: Vitamin D resistance describes a spectrum of conditions in which individuals fail to achieve expected biological responses to vitamin D despite supplementation and/or apparently adequate serum 25-hydroxyvitamin D [25(OH)D] concentrations and sun exposure. While rare hereditary forms such as Hereditary Vitamin D-Resistant Rickets (HVDRR) are well-characterized, emerging evidence suggests that acquired resistance may contribute to suboptimal responsiveness in a broader clinical population. Contributing factors include genetic variation in vitamin D metabolism and receptor pathways, chronic inflammation, metabolic dysregulation, micronutrient cofactor insufficiencies, and environmental exposures. This review synthesizes current understanding of vitamin D resistance mechanisms, diagnostic challenges, and implications for personalized supplementation strategies. We propose an operational definition of vitamin D resistance as a state of inadequate physiological response to vitamin D despite achieving conventionally sufficient 25(OH)D levels, best assessed using response-based markers such as PTH suppression, calcium handling, and clinical endpoints. We further outline a pragmatic, systems-based evaluation framework that incorporates endocrine, inflammatory, metabolic, medication-related, and micronutrient determinants to guide individualized dosing and monitoring.

Abstract: Background/Objectives: Chemsex is defined as the intentional use of psychoactive substances to enhance or prolong sexual activity, predominantly observed among men who have sex with men. It has emerged as a notable behavioral and public health concern due to its association with high-risk sexual practices, psychiatric morbidity, and somatic complications. Despite increasing recognition, global prevalence estimates vary widely (3–52.5%) due to differences in study populations and methodology. Commonly used substances include synthetic cathinones, amphetamines/methamphetamines, MDMA, GHB/GBL, ketamine, alkyl nitrites, and PDE-5 inhibitors. Methods: A narrative review was conducted using PubMed through December 11, 2025. Search terms combined chemsex-related terminology, substance names, and health outcomes. Recent English-language publications (2020-2025) were prioritized. Evidence was synthesized thematically across epidemiology, health complications, motivations, and interventions. Results: Chemsex is strongly associated with unprotected sex, multipartner encounters, and prolonged intercourse, leading to significantly increased rates of HIV, syphilis, gonorrhoea, and chlamydia. Psychiatric complications include depression, anxiety, compulsive sexual behavior, and psychosis, with higher risks in individuals engaging in slamming or polysubstance use. Somatic complications vary by substance and include cardiovascular disease, hyponatremia, rhabdomyolysis, ulcerative cystitis, methemoglobinemia, and overdose. Motivational factors extend beyond sexual enhancement and include minority stress, internalized and externalized stigma, and maladaptive coping mechanisms. Integrated interventions combining harm reduction, cognitive-behavioral therapy, peer-led services, and pharmacotherapy, alongside digital health tools to support PrEP adherence and risk reduction, show promise in mitigating these harms. Conclusions: Chemsex represents a complex interplay of biological, psychological, and sociocultural factors that contribute to elevated STI risk and psychiatric and somatic morbidity. Addressing chemsex requires destigmatized, multidisciplinary approaches that integrate behavioral, pharmacological, and community-based interventions. Digital health innovations can further enhance engagement, risk reduction, and access to timely care.

Abstract: Revision total knee arthroplasty (rTKA) is a technically demanding procedure that fre-quently relies on stems, augments, metaphyseal cones and constrained implants to restore knee alignment and stability. In carefully selected cases with preserved metaphyseal bone stock and competent collateral ligaments, robotic assistance allows a bone-preserving strategy in which alignment, joint line height, and soft-tissue balance are restored using conventional posterior-stabilized components with short cemented stems rather than higher invasive and constrained constructs. This technical note describes a step-by-step surgical workflow using the Mako robotic system (Stryker) to revise failed primary TKA associated with minimal metaphyseal bone loss to rTKA with conventional posterior-stabilized components with short cemented stems within a functional-alignment framework. The workflow integrates CT-based three-dimensional planning, registration on in situ implants, real-time gap assessment, and precise robotic bone preparation to correct deformity and to restore stability while minimizing additional bone resection. In this setting, limited tibial metaphyseal defects are managed with impacted autologous cancellous graft, and stable fixation is achieved with short cemented stems. This reproducible robotic-assisted approach is intended as a bone-preserving option for selected rTKA cases associated with minimal bone loss and as a conceptual bridge between robotic-assisted primary and conventional revision TKA performed with mechanical technique and alignment.

Abstract:

Embolization of intracardiac occlusion devices is an uncommon but potentially serious complication requiring interventional radiology management. We report a case of delayed migration of an Amplatzer patent foramen ovale occluder into the infrarenal abdominal aorta. An 18-year-old woman presented with acute abdominal pain one month after percutaneous PFO closure. Contrast-enhanced computed tomography performed for suspected intra-abdominal bleeding incidentally revealed the embolized device in the infrarenal aorta, with preserved renal artery patency. After multidisciplinary evaluation, endovascular retrieval was planned. Via right common femoral artery access, the device was successfully captured using a snare system and removed through a large-bore introducer sheath without complications. Final angiography confirmed normal aorto-iliac patency. This case highlights the importance of cross-sectional imaging and demonstrates that endovascular snare retrieval is a safe and effective first-line treatment for delayed device embolization.

Abstract: Unlike skeletal Class I and II patients, the application of maxillomandibular advancement (MMA) in skeletal Class III patients with obstructive sleep apnea (OSA) is not well documented. The aim of this scoping review was to explore the variations and outcomes of MMA techniques in this unique subgroup. A comprehensive search of PubMed, Embase, Cochrane and LILACS databases were conducted for articles published up to May 2025. Nine studies met the inclusion criteria. Three main variations of MMA were identified: (1) Bimaxillary advancement, which provides the most significant airway enlargement across all pharyngeal regions but carries the highest risk of facial aesthetic distortion; (2) Maxillary advancement with mandibular auto-rotation, a less invasive option suited for patients with isolated maxillary retrusion and symmetrical mandibular anatomy; (3) Maxillary advancement with mandibular setback, which addresses aesthetic concerns in patients with mandibular excess but may compromise oropharyngeal airway space. All variations were reported to be effective in treating OSA but with different considerations. Surgical planning for skeletal Class III patients with OSA should be individualized based on craniofacial morphology, anatomical site of airway obstruction, and aesthetic considerations. A decision flowchart was shared in this study.

Abstract: Background: The antimicrobial peptide LL-37 has emerged as a key mediator linking innate and adaptive immunity and has been implicated in the pathogenesis of immune-mediated inflammatory diseases. While circulating levels of LL-37 and anti-LL-37 antibodies have been investigated in several conditions, their presence and relevance within the local joint microenvironment remain insufficiently explored. This study aimed to evaluate anti-LL-37 antibodies in synovial fluid from patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), and knee osteoarthritis (GoA), and to analyze their associations with pro-inflammatory cytokines. Methods: Synovial fluid samples were obtained from patients with PsA, RA, GoA, and from healthy controls. Levels of anti-LL-37 antibodies, IL-1β, IL-6, and IL-23 were measured using enzyme-linked immunosorbent assay (ELISA). Correlation analyses were performed to assess relationships between anti-LL-37 antibodies and cytokine levels. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of anti-LL-37 antibodies. Results: Anti-LL-37 antibody levels were significantly elevated in synovial fluid from patients with PsA compared to RA, GoA, and healthy controls. Patients with RA exhibited lower anti-LL-37 levels despite pronounced elevations of IL-1β and IL-6. In GoA, anti-LL-37 concentrations were comparable to those of healthy controls. A strong positive correlation between anti-LL-37 antibodies and IL-23 was observed in PsA, whereas correlations with IL-1β and IL-6 were more prominent in RA. ROC analysis demonstrated moderate diagnostic accuracy of anti-LL-37 antibodies in distinguishing PsA from healthy controls, but limited utility in RA and GoA. Conclusions: The findings support a disease-specific role of anti-LL-37 antibodies in the immunopathogenesis of psoriatic arthritis and highlight their association with the IL-23/Th17 axis within the synovial microenvironment. Anti-LL-37 antibodies may serve as a complementary biomarker for PsA and provide further insight into the distinct immunological mechanisms underlying inflammatory versus degenerative joint diseases.

Abstract:

Objectives: We investigated the effects of Continuous Positive Airway Pressure (CPAP) on blood pressure (BP) and vigilance in taxi drivers with obstructive sleep apnea (OSA). Methods: Taxi drivers aged ≥60 years were recruited for polysomnography. Those diagnosed with OSA underwent 6 months of CPAP therapy. Baseline and follow-up assessments included 24-hour ambulatory blood pressure monitoring (ABPM) and the psychomotor vigilance test (PVT). Results: Among the 32 participants, 22 (68.8%) were diagnosed with OSA (median age 63.0 [62.0–65.0] years; 21 males). The average CPAP adherence was 3.1±2.3 hours per night, with 23.5% using CPAP for more than 4 hours per night. There were no significant changes in 24-hour mean systolic ABPM (125.9 [116.8–134.9] mmHg to 126.0 [118.3–133.7] mmHg; p=0.93) or reaction times measured by PVT (2.0 [0.0–3.0] lapses to 2.0 [1.0–3.0] lapses; p=0.82) after CPAP therapy. Conclusion: A high prevalence of OSA was observed among taxi drivers. CPAP adherence was suboptimal and did not result in significant improvements in BP or vigilance.

Abstract: Background/Objectives: Atrial fibrillation (AF) is closely associated with adverse remodeling of the left atrium (LA). This study evaluated the impact of LA diameter on long-term outcomes following radiofrequency ablation (RFA) of the pulmonary veins and assessed LA and left ventricular (LV) remodeling over a seven-year follow-up period. Methods: A total of 117 patients with symptomatic, drug-refractory AF underwent RFA. Structural remodeling was evaluated using echocardiography. Long-term outcomes were categorized using the Pulmonary Vein Isolation Outcome Degree (PVIOD), a four-level classification reflecting procedural and clinical success. Results: After seven years, 32.5% of patients who achieved successful sinus rhythm maintenance after a single RFA (PVIOD 1) demonstrated significant reverse remodeling of LA and LV. LA diameter decreased from 39.3±0.6 mm to 36.5±0.6 mm (p< 0.001); LV end-diastolic diameter (LVEDD) from 53.1±0.6 mm to 50.9±0.7 mm (p=0.008); LV end-systolic diameter (LVESD) from 34.7±0.8 mm to 32.0±0.1 mm (p=0.005); and LV ejection fraction (LVEF) increased from 56.8±0.8% to 62.1±1.1% (p< 0.001). Among patients with long-term success after multiple procedures (PVIOD 2; 29.1%), LA diameter decreased significantly from 41.9±0.7 mm to 40.2±0.6 mm (p=0.044), without significant ventricular changes. Patients achieving clinical success (PVIOD 3; 14.5%) showed no significant structural changes. Those with procedural and clinical failure (PVIOD 4; 23.9%) exhibited progressive negative remodeling: LA diameter increased from 44.7±0.7 mm to 47.4±0.7 mm (p=0.006); LVEDD from 52.8±0.9 mm to 57.1±0.6 mm (p< 0.001); LVESD from 36.5±1.1 mm to 40.7±1.2 mm (p=0.006); and LVEF decreased from 50.7±1.7% to 43.8±1.8% (p=0.004). Conclusions: Early and successful single RFA performed in patients with normal LA diameter is associated with complete reverse remodeling and prevention of AF recurrence. As LA size increases, the likelihood of achieving durable procedural success decreases, emphasizing the importance of timely intervention before significant left atrial enlargement develops.

Abstract: The increasing global temperatures and frequency of heatwaves due to climate change have elevated the risk of chronic dehydration, particularly in arid regions. This study details the development and production process of a novel vitamin-fortified water designed to address this issue by providing essential hydration alongside key vitamins and electrolytes. The formulation centers on a concentrated vitamin extract comprising Ascorbic Acid (Vitamin C), Riboflavin (Vitamin B2), 25-Hydroxycholecalciferol (Vitamin D3), and α-Tocopherol Acetate (Vitamin E). The extract is stabilized using Polyethylene Glycol (PEG)-based surfactants and Rosmarinic acid as a natural preservative. This concentrate is then diluted in biologically active water (BAW) to produce the final beverage. The resulting product is a colorless, palatable liquid with a pH of 6.0, intended to support hydration, bolster the immune system, and provide essential micronutrients. This Work outlines both conventional solution preparation and a non-conventional, integrated mixing process for the vitamin concentrate.

Abstract: Post-inflammatory hyperpigmentation (PIH) is a common pigmentary disorder characterized by excessive melanin production following skin inflammation. Histamine, a key inflammatory mediator, is known to stimulate melanogenesis via H2 receptors; however, the underlying calcium signaling mechanisms remain largely unexplored. In this study, we investigated the role of the ORAI1-STIM1 complex in histamine-induced melanogenesis using B16F10 melanoma cells and normal human epidermal melanocytes (NHEMs). Histamine (10–30 μM) significantly increased melanin content (2.5–2.8-fold), an effect specifically abolished by the H2 antagonist famotidine. Notably, while acute histamine application failed to trigger immediate calcium influx, chronic exposure significantly enhanced store-operated calcium entry (SOCE) capacity by approximately 2.8-fold, providing evidence for a functional remodeling of the Ca2+ signaling machinery. Histamine-induced melanogenesis was significantly suppressed by intracellular calcium chelation, pharmacological inhibition of ORAI1 (BTP-2 or Synta-66), and siRNA-mediated silencing of ORAI1 or STIM1, but not ORAI2, ORAI3, or STIM2. Our findings demonstrate that chronic histamine exposure drives hyperpigmentation through ORAI1-STIM1-mediated SOCE remodeling, establishing this complex as a promising therapeutic target for the treatment of PIH and related inflammatory pigmentary disorders.

Abstract: Diffuse large B-cell lymphoma (DLBCL) is one of the most frequent subtypes of non-Hodgkin lymphoma (NHL). In approximately 40% of the patients, the prognosis and clinical evolution is unfavorable. This study is a proof-of-concept computer vision exercise to support the feasibility of predicting the prognosis of DLBCL using only hematoxylin and eosin (H&E) histological images and deep learning. A conventional series of DLBCL of 114 cases was split into two prognostic groups according to the overall survival (curve fitting and slope analysis): patients who died before the first 2 years (“Dead 2-years”, b1 = -0.054), and the others (b1 = -0.003). Twenty different convolutional neural networks (CNN) were used, and explainable artificial intelligence (XAI) was used to identify the areas of the images that the network used for classification. The final model based on DarkNet-19 predicted prognosis groups with high performance (test set accuracy = 96.26%). The other performance parameters were precision (94.46%), recall (95.02%), false positive rate (3.07%), specificity (96.93%), and F1 score (94.74%). XAI, including grad-CAM, occlusion sensitivity, and image-LIME confirmed that the CNN was focusing on the correct areas. Correlation with the clinicopathological characteristics found that the Dead < 2-years group was correlated with stage III-IV, International Prognostic Index (IPI) High + High/intermediate, progressive disease, non-GCB cell-of-origin, CD10-, BCL2+, and EBER+. Analysis of the immune microenvironment, cell cycle, and germinal center markers showed that Dead < 2-years had higher IL10, PD-L1, and CD163, and lower E2F1 protein expressions. In conclusion, the overall survival of DLBCL can be predicted using H&E histological images and deep learning. The trained CNN could be used as pre-trained CNN model for transfer learning in the future.