A targeted drug conjugate derived from GNS561 and a Pt(II) moiety for PPT1-mediated lysosomal autophagy inhibition in triple-negative breast Cancer.

A pH-sensitive nanococktail enabled cancer stem cell elimination, deep tumour penetration, and tumour shrinkage.

A Simultaneous Assessment of Efficacy and Safety of Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Lung Disease.

This scoping review aimed to evaluate the effects of anabolic-androgenic steroids (AAS) administration on oral health in humans, distinguishing between medical indications (e.g., replacement therapy) and abuse, while mapping their impact on oral conditions and identifying gaps in knowledge. A systematic search was conducted using PubMed, Cochrane Library, and Virtual Health Library databases. Search terms included keywords related to AAS, testosterone and specific oral health conditions such as dental caries, tooth loss/edentulism, periodontal disease, oral trauma, and oral cancer. Studies were screened and selected based on inclusion criteria: adult humans, AAS use and reported oral health outcomes, with findings interpreted separately according to medical indication (replacement vs. abuse). After screening, eight studies met the inclusion criteria. In the context of AAS abuse, users exhibited poorer periodontal health, with higher rates of severe periodontitis, increased gingival inflammation, and greater gingival thickness. Oral trauma studies indicated a higher frequency of temporomandibular dysfunction and malocclusion among users. A severe adverse event (Stevens-Johnson Syndrome) was also reported in one case of AAS abuse. Conversely, studies addressing medical indications found that therapeutic AAS administration was associated with reduced mucosal toxicity, decreased pain, and remission of aphthous lesions. No studies evaluating dental caries, tooth loss/edentulism, or cleft lip and palate were identified. The effect of AAS on human oral health is critically dependent on the context of administration. AAS abuse is associated with significant oral pathology, notably the increased severity of periodontal disease and risk of severe mucocutaneous adverse events. Conversely, AAS administered under medical indication demonstrated therapeutic potential in reducing treatment-related toxicity (e.g., in oral cancer) and promoting the resolution of recurrent soft tissue lesions (e.g., aphthous ulcers). It is recommended that future studies adopt well-designed sampling strategies in longitudinal studies to enhance clinicians' and researchers' understanding of its effects and mechanisms, ultimately enabling evidence-based recommendations or advisories for or against its use for oral conditions. Health professionals should be aware of the distinct oral health risks and benefits associated with AAS. AAS abuse represents a critical risk factor for severe periodontal pathology and potential mucocutaneous adverse events. Conversely, low-level evidence supports recognizing the therapeutic potential of medically indicated AAS as supportive care for conditions like chemotherapy/radiotherapy-induced mucositis and recurrent soft tissue lesions. Identifying gaps in the literature highlights the need for broader research to ensure the safe monitoring of individuals who use these substances.

Safety and efficacy of staged, bilateral magnetic resonance-guided focused ultrasound pallidothalamic tractotomy for motor complications of Parkinson's disease: a prospective, multicentre, single-arm trial.

Patients with moderate-to-severe atopic dermatitis (AD) and significant comorbidities are frequently excluded from randomized clinical trials, limiting the applicability of evidence to these clinically complex patients. We evaluated the effectiveness and safety of tralokinumab in this setting. Multicenter retrospective study including adults with moderate-to-severe AD treated with tralokinumab (300mg every 2weeks) in Spanish tertiary hospitals (June 2022-December 2025). Special populations included patients with malignancies, advanced cardiovascular or renal disease, chronic infections, or neurologic disorders. Outcomes included Eczema Area and Severity Index (EASI), pruritus NRS, safety events, and treatment optimization. Analyses were descriptive. Twenty-one patients (aged 27-90years) with high multimorbidity burden were included. Comorbidities comprised malignancies (n = 9), advanced heart disease (n = 7), neurologic disorders (n = 4), chronic kidney disease (n = 2), latent tuberculosis (n = 2), and HIV (n = 2). Mean EASI decreased from 19.3 to 3.45 (~ 82% reduction) and pruritus Numeric Rating Scale (NRS) from 7 to 2 (~ 71% reduction) after a mean follow-up of 24.6months. Approximately 70% achieved EASI ≤ 3 and 50% EASI 0-1. Median follow-up was 24.6months. Dose interval extension was feasible in 33.3% of patients. No tumor progression, infection reactivation, major cardiovascular events, or severe adverse events were observed. Tralokinumab showed sustained effectiveness and a favorable safety profile in clinically complex patients with AD. These real-world findings support IL-13 blockade as a valuable therapeutic option for multimorbid populations that are underrepresented in clinical trials.

Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder caused by mutations in SERPINA1 that result in insufficient circulating alpha-1 antitrypsin (AAT) and progressive lung and liver diseases. Adeno-associated virus (AAV)-mediated gene therapy offers the potential for durable AAT expression; however, achieving therapeutic serum concentrations (≥11 µM) at clinically acceptable vector doses remains a major challenge. Here, we evaluated multiple AAV vector design strategies to enhance AAT expression and increase vector potency, thereby reducing the required dose to levels below those associated with severe adverse events. Using AAV1- and AAV8-based platforms, we compared promoter and enhancer configurations, codon optimization of the SERPINA1 transgene, single-stranded versus self-complementary vector genomes, alternative polyadenylation signals, and an engineered oxidation-resistant AAT variant. Across mouse and ferret models, the chicken β-actin expression cassette consistently produced higher AAT levels than a liver-specific promoter variant despite comparable vector biodistribution, reflecting superior intrinsic transcriptional activity or an important contribution. Codon optimization did not enhance expression and, in some cases, modestly reduced AAT levels. Self-complementary AAV vectors exhibited reduced overall expression due to required promoter truncation, yielding lower transgene output than full-length single-stranded constructs. Modifications to polyadenylation signals or enhancer combinations did not improve expression. An oxidation-resistant AAT variant resulted in lower circulating levels but may retain therapeutic potential through enhanced functional stability. Collectively, these findings demonstrate that promoter strength and cassette architecture are dominant determinants of AAV-AAT potency and that full-length, single-stranded vectors with robust regulatory elements provide the highest expression. This work defines key parameters governing AAT expression invivo and provides a foundation for next-generation AAV designs aimed at achieving therapeutic efficacy at safer, lower vector doses for the treatment of AATD.

Liver cancer is a leading cause of cancer-related mortality worldwide. Clinical use of the first-line drug sorafenib is limited due to drug resistance and severe adverse effects. The current study aimed to synthesize a series of N-arylated thiophene-based 1,3,4-oxadiazole derivatives containing a carbamothioate moiety (7a-7d) as potential anticancer agents with improved efficacy and safety profiles. Derivatives were synthesized via coupling of thiophene-based 1,3,4-oxadiazole (compound 1) with various electrophiles, yielding 62-86%. The structures of all derivatives were established based on FT-IR, 1H NMR, 13C NMR, and EI-MS. The in-vitro anticancer effect of all derivatives was assessed using the MTT assay against the HepG2 cancer cell line and their hemolytic safety was assessed on human red blood cells. All derivatives exhibited cytotoxicity with minimal hemolytic effects. Derivative 7b (2,6-dimethyl) exhibited excellent activity by reducing cell viability of 33.96 ± 2.47% at 100 μg/mL and minimal hemolysis (1.20 ± 0.01%) with a high selectivity index (SI) of 28.3, similar to sorafenib (34.32 ± 1.91%, SI = 27.45). Derivatives 7a (phenyl) and 7d (ethyl) showed moderate activity and 7c (fluoro) was the least potent. Thiophene-based oxadiazole-coupled carbamothioate derivatives, particularly 7b, demonstrate enhanced anticancer efficacy and safety compared to sorafenib, representing promising candidates for targeted liver cancer therapy.

Nigakinone enhances FXR expression to synergize with irinotecan in suppressing colorectal cancer cells and xenografts.

Although programmed cell death 1 inhibitors (PD1i) are recommended in guidelines for relapsed/refractory extranodal NK/T-cell lymphoma (ENKTL), their role in frontline therapy remains unclear. In this retrospective, multi-center study of 755 newly diagnosed ENKTL patients, 17.9% received first-line PD1i. Despite harboring more adverse risk features, the PD1i group showed significantly improved progression-free survival (hazard ratio = 0.62, p = 0.007) and overall survival (hazard ratio = 0.55, p = 0.027) after a median follow-up of 32.9 months. The benefit was also observed in key subgroups (non-upper aerodigestive tract, advanced stage, intermediate/high-risk). Conventional multivariate Cox regression before propensity score matching, robust multivariate Cox analysis after matching, and the time-varying Cox model employed in landmark analysis consistently demonstrated that PD1i therapy served as an independent favorable prognostic factor for both progression-free survival and overall survival. The random forest algorithm revealed enhanced efficacy with PD1i-asparaginase combination therapy, showing about a 50% reduction in event probability, particularly in advanced-stage and intermediate/high-risk patients. Multi-state survival modeling indicated PD1i primarily delays disease progression rather than post-progression survival. Safety data showed that adding PD1i to asparaginase-based chemotherapy resulted in an expected increase in hematologic toxicities, but with a reduced risk of severe/fatal infections and rare severe immune-related adverse events, demonstrating a favorable risk-benefit profile. Overall, in this study, frontline PD1i, particularly in combination with asparaginase, yielded significantly improved outcomes and demonstrated a manageable safety profile in intermediate-/high-risk and advanced ENKTL. This evidence supports its incorporation into first-line treatment and underscores the need for prospective randomized trials.

In patients with severe ocular surface disease (OSD) and cornea and cataract-related vision impairment, where the risk of allograft rejection after allogeneic corneal transplantation is unacceptably high and cataract surgery impossible because of corneal opacity, cataract extraction may still offer meaningful improvement in vision-related quality of life. We describe ipsilateral, nonrotational autokeratoplasty (INRA) as option to perform open-sky cataract surgery after removal of the central cornea and prevent immune responses by placing back the original host cornea. This report presents 2 patients with only 1 functional eye, cataract and severe OSD (Lyell syndrome, chemical burn) undergoing INRA to enable cataract surgery as an alternative approach to visual rehabilitation, aiming to avoid high-risk corneal transplantation. Both patients had a small central zone of relative corneal clarity. This is the first report of INRA for concomitant cataract surgery. Postoperatively, both visual acuity and patient-reported visual satisfaction improved. In 1 case, delayed wound healing was noted and successfully managed with standard treatments. No other severe complications, adverse events, or rejection episodes were observed. Although INRA does not address corneal vision impairment, it allows effective cataract management in patients with relative central corneal clarity and otherwise very high risk for corneal allograft failure.

Laser tattoo removal often requires multiple treatment sessions despite advances in picosecond laser technology. Multimodal approaches aimed at improving treatment efficiency are increasingly being explored. This study retrospectively evaluated the clinical outcomes of a vacuum-assisted multimodal picosecond laser tattoo removal protocol.A retrospective observational case series was conducted including 16 tattoos that completed treatment with standardized photographic follow-up. The protocol combined fractional ablative laser pretreatment (1064nm, 3-5 stacks), followed by two full-beam picosecond 1064nm passes with application of a vacuum-assisted device between passes. Standardized images were acquired using the Quantificare imaging system. Treatment outcomes were independently evaluated by three blinded experts. Kirby-Desai estimated treatment sessions were additionally calculated as a historical comparative reference.Sixteen tattoos completed treatment and were included in the final analysis. Mean pigment clearance exceeded 90% following a mean of 3.19 treatment sessions, with high interobserver agreement among blinded evaluators. The observed number of treatment sessions was lower than Kirby-Desai estimated values used as historical reference. No severe long-term adverse events were observed.This retrospective case series suggests that a vacuum-assisted multimodal picosecond laser tattoo removal protocol may be associated with high tattoo clearance rates using relatively few treatment sessions. However, given the retrospective design, absence of a control group, and multimodal nature of the protocol, the independent contribution of vacuum assistance cannot be determined. Prospective controlled studies are needed to further evaluate the role of adjunctive mechanical approaches in tattoo removal optimization.

ObjectiveTalaromyces marneffei (TM) represents a major opportunistic infection among People living with HIV (PLWH) in Southeast Asia and southern China. This study aimed to evaluate the efficacy and safety of Albuvirtide (ABT, currently licensed only in China)-based antiretroviral regimens during the advanced stage of infection in this understudied population.MethodsWe conducted a longitudinal case series from June 2022 to March 2024 at two hospitals in Guangxi, China. The study included treatment-naive HIV/TM co-infected patients who initiated ABT-based antiretroviral therapy combined with oral background regimens (predominantly dolutegravir/lamivudine or bictegravir/emtricitabine/tenofovir alafenamide). Analyses and findings evaluated after 6 weeks of treatment included changes in HIV viral load, CD4 + T-cell count, and CD4/CD8 ratio. Data were analyzed using Wilcoxon signed-rank and McNemar's tests.ResultsA total of 52 patients were included. Excluding one patient lost to follow-up, the 6-week survival rate was 98.0% (50/51), with a single mortality attributed to advanced disease. In the 50 patients analyzed, the median viral load decreased rapidly from 274,500 (IQR: 52,775-794,874) to 119.5 (IQR: 40-464.5) copies/mL (P < 0.001). The median CD4 + T-cell count increased significantly from 14.0 (IQR: 5.0-32.0) to 83.5 (IQR: 35.0-127.75) cells/μL (P < 0.001). The CD4/CD8 ratio showed an improving trend (0.065 to 0.100, P = 0.058). No severe adverse events related to the study drugs were observed.ConclusionFindings from this small case series suggest that ABT-based regimens demonstrated a favorable safety profile and achieved rapid viral suppression during the critical advanced stage of HIV/TM co-infection. These findings suggest that adding parenteral ABT to oral background regimens provides a feasible and intensified treatment strategy to stabilize critically ill patients, particularly those with potential gastrointestinal dysfunction.

Unplanned extubations are adverse events with multifactorial causes, involving both patient characteristics and organizational features in Paediatric Intensive Care Units (PICUs). To identify the main clinical and contextual determinants associated with unplanned extubations in PICU patients. We conducted a case-control retrospective observational study at a paediatric hospital in Eastern Andalucia (Spain). Cases were patients who experienced an unplanned extubation, and controls were those who did not during the same period. A total of 121 active cases and 275 controls were included, yielding a rate of 5.07 events per 100 ventilated patients. For the 2902 invasively ventilated children, 147 unplanned extubations occurred in 121 children (4.17% of children experienced at least one event). Unplanned extubations occurred more frequently in patients receiving assisted ventilation (OR = 2.52; 95% CI: 1.56-4.07). The mean additional length of stay in the PICU for cases was 7.5 days. Independent predictors for unplanned extubations included male sex (OR = 0.87; 95% CI: 0.47-1.63), older age (OR = 1.01; 95% CI: 0.99-1.02), use of assisted-spontaneous ventilatory modes (OR = 2.47; 95% CI: 1.18-5.19), lower doses of midazolam (OR = 24.28; 95% CI: 1.57-11.62), and nurse overallocation (OR = 2.05; 95% CI: 1.19-3.53). Unplanned extubations in PICU are influenced by both clinical factors and organizational aspects of care. Notably, most predictors identified (e.g., sedation practices, nurse staffing) are modifiable, indicating the potential for targeted interventions to reduce this adverse event. Preventing unplanned extubations is critical for safeguarding paediatric patients. By optimizing nursing ratios, sedation regimens, and care protocols, PICUs can reduce the incidence of accidental extubations, thereby improving patient outcomes and minimizing prolonged lengths of stay. These findings should be used by healthcare managers to systematically evaluate the consequences of a severe adverse effect such as unplanned extubations (UE) and introduce quality improvement actions to minimize the consequences on patient safety and PICU outcomes.

The prolonged use of conventional steroidal and non-steroidal anti-inflammatory drugs, as well as laxatives, often leads to severe adverse effects and toxicity, posing significant health risks. To address these challenges, we formulated a novel therapy based on (multi)metallic nanoparticles (MMNPs) green-synthesized from agricultural by-products, namely plantain peels (Musa paradisiaca) and Aloe vera gel. The MMNPs were characterized through UV-visible spectrophotometry, energy-dispersive X-ray spectroscopy (EDX), and dynamic light scattering (DLS), revealing nanoparticle sizes between 250 and 400nm. These MMNPs were incorporated into effervescent suppositories using Mangifera indica almond butter as a base to facilitate rectal administration and induce laxative effects in situ. The anti-inflammatory and laxative properties of the MMNPs were evaluated in guinea pigs (Cavia porcellus) used as animal model, in which inflammation and constipation were induced by formaldehyde and loperamide, respectively. Remarkably, at 60min, the effervescent suppositories loaded with MMNPs and MMNPs enriched with ash demonstrated inhibition rates of 74.13% and 69.39%, respectively, for paw edema, outperforming the reference drug indomethacin, which showed an inhibition rate of 73.27%. Furthermore, the effervescent suppositories effectively triggered a laxative response, combating constipation with notable efficiency. This study demonstrates the potential of green-synthesized MMNPs derived from Musa paradisiaca peels and Aloe vera gel as a promising, eco-friendly therapeutic alternative for managing both inflammation and constipation, minimizing the risk of side effects associated with conventional treatments.

The optimal approach between perioperative chemotherapy (CT) versus preoperative chemoradiotherapy (CRT) for esophageal carcinoma remains debated. This meta-analysis compares the safety and efficacy of CT versus CRT in resectable esophageal and gastroesophageal junction carcinoma. Electronic databases were systematically searched for eligible randomized controlled trials (RCTs) that enrolled adult patients (aged ≥ 18 years) with histologically confirmed, resectable esophageal or gastroesophageal junction carcinoma, directly compared perioperative CT with preoperative CRT, and reported at least one outcome of interest. Meta-analysis was conducted using RevMan 5.4 with a random-effects model. Hazard Ratios (HRs) were pooled for time-to-event outcomes, and risk ratios (RR) for dichotomous endpoints. Eight RCTs were included. Compared with CRT, CT had significantly reduced R0 resection rates (RR 0.94, 95% CI 0.89, 0.99) and a lower pathologic complete response (RR 0.27, 95% CI 0.13, 0.58). No statistically significant differences were observed in overall survival, progression-free survival, postoperative mortality, or severe adverse events. There was a trend toward greater benefit of CRT in squamous cell carcinoma; however, the test for subgroup differences did not attain statistical significance. This meta-analysis suggests that CRT improves local tumor control by increasing R0 resection rates and complete response rates, but without a clear survival advantage over CT. This meta-analysis further highlights the need for an updated multidisciplinary framework and highlights the importance of biomarker-driven strategies in future research.

Lung cancer is still among the most malignant cancers, with immunotherapy becoming a ground-breaking treatment option. The ICIs and other immunotherapeutic drugs usually cause severe immune-related adverse effects curtailing their therapeutic efficacy. Meeting this challenge, Nano medicine-based drug delivery systems have gained considerable interest as they hold the promise of increasing therapeutic benefits at the same time as reducing toxicity. This chapter discusses the complex balance between the effectiveness and toxicity of lung cancer immunotherapy, underlining the application of nanotechnology in maximizing drug delivery. Nano carriers like liposomes, polymeric nanoparticles, dendrites, and lipid-based systems have demonstrated the capacity to augment the bioavailability of pharmaceuticals, facilitating tumour-specific environments, and alleviating systemic side effects. Other options suggest that stimuli-responsive and ligand-functionalized Nano platforms can provide spatial control over the immune response by enhancing infiltration to the tumour site while reducing toxicity to healthy organs. On the battlegrounds of nanomedicine, inhibiting resistance mechanisms consolidated with immune checkpoint inhibitors and conventional chemotherapeutics has conferred better therapeutic responses upon the patient. Its stability, bio-distribution, and regulatory pathway concerns still challenge clinical translation. The chapter discusses recent advances in preclinical and clinical testing and describes the development of Nano medicine-based regulatory T-cell-directed immunotherapy for lung and lung-associated cancers. The problems concerning both toxicity and the application of nanotechnology for targeting therapy will open new avenues toward developing safer and more effective antitumor immunotherapeutic regimes for lung cancer.

Effectiveness of interventions to promote couples-based HIV testing and family health during pregnancy and postpartum in Kenya: a multicentre, couples-based, randomised controlled trial.

Chronic skin defects, particularly venous leg ulcers, impose a substantial clinical and socio-economic burden. This single-arm observational study was undertaken to describe the healing dynamics, pain outcomes, feasibility and tolerability of adjuvant visible incoherent polarised (VIP) phototherapy in patients with chronic skin defects who were managed with full standard care, and to examine whether outcomes varied with the principal clinical problem and treatment duration.A prospective, single-arm cohort of 50 patients (38 females, 12 males; mean age 69.4 years) was observed. Adjuvant VIP phototherapy (626nm; 2 mW/cm2) was applied alongside the standard conservative and surgical wound care received by all patients, for 10-20min per field, two to three times daily; the continuous emission mode was changed to a pulsed mode (5Hz) after 7-10 days. Wound area was assessed planimetrically in a representative case, and pain on a 0-10 numeric scale. No sham-irradiated control group was included.Positive healing dynamics were recorded in 92% of the cohort and complete defect closure in 52% (n = 26). In the chronic-pain subgroup (n = 17), pain was reduced in 12 patients and resolved in 5. Improvement was associated with the principal clinical problem (χ2 = 10.406; df = 3; p = 0.015) and with therapy duration (χ2 = 8.630; df = 3; p = 0.035). Two patients reported mild, transient local reactions; no severe adverse events occurred.In this uncontrolled cohort, adjuvant VIP phototherapy was feasible, well tolerated and accompanied by favourable healing and pain outcomes. Because no control group was studied, these findings cannot be attributed to the light itself and are hypothesis-generating; randomised, sham-controlled trials are required.

Breast cancer remains a global challenge, with rising incidence rates. While treatment advancements have improved outcomes, systemic administration of cytostatic agents continues to cause severe adverse effects, including myelosuppression, heart failure, and infertility, due to non-specific biodistribution. Nanoparticle-based drug delivery systems have been explored as an alternative approach to improve therapeutics delivery and reduce non-specific effects. Zinc-based nanoparticles demonstrate ability to induce cytotoxic responses in cancer cells in vitro, making them suitable systems for probing cell-type-specific effects. In this study, we evaluated the in vitro cytotoxic effects of spherical zinc peroxide (ZnO₂) nanoparticles (20-80 nm and 50-300 nm), commercial ZnO nanoparticles, and tetrapodal ZnO (T-ZnO) microparticles in MCF-7 breast cancer cells and RMF-EG fibroblasts. ZnO₂ nanoparticles demonstrated dose-dependent cytotoxicity (1 µg/mL-10 mg/mL), inducing a significantly higher death rate of cancer cells than normal fibroblasts, which retained >75% viability at comparable doses. Flow cytometry investigations revealed that ZnO₂ nanoparticles exhibited preferential cellular uptake in MCF-7 cells as compared to fibroblasts. Overall, these findings indicate different cytotoxic responses of ZnO-based micro and nanoparticles between MCF-7 cells and RMF-EG fibroblasts under in vitro conditions. Further studies are required to validate these observations in more complex biological systems and to clarify the underlying mechanisms.