Clinical Investigation Research Articles

Clinical investigation of Ramsay–Hunt syndrome with glossopharyngeal and vagal nerve involvement

Clinical investigation of Ramsay–Hunt syndrome with glossopharyngeal and vagal nerve involvement

Evaluation of Human Platelet Lysate as an Alternative to Fetal Bovine Serum for Potential Clinical Applications of Stem Cells from Human Exfoliated Deciduous Teeth

In recent years, there has been a surge in demand for and research focus on cell therapy, driven by the tissue-regenerative and disease-treating potentials of stem cells. Among the candidates, dental pulp stem cells (DPSCs) or human exfoliated deciduous teeth (SHED) have garnered significant attention due to their easy accessibility (non-invasive), multi-lineage differentiation capability (especially neurogenesis), and low immunogenicity. Utilizing these stem cells for clinical purposes requires careful culture techniques such as excluding animal-derived supplements. Human platelet lysate (hPL) has emerged as a safer alternative to fetal bovine serum (FBS) for cell culture. In our study, we assessed the impact of hPL as a growth factor supplement for culture medium, also conducting a characterization of SHED cultured in hPL-supplemented medium (hPL-SHED). The results showed that hPL has effects in enhancing cell proliferation and migration and increasing cell survivability in oxidative stress conditions induced by H2O2. The morphology of hPL-SHED exhibited reduced size and elongation, with a differentiation capacity comparable to or even exceeding that of SHED cultured in a medium supplemented with fetal bovine serum (FBS-SHED). Moreover, no evidence of chromosome abnormalities or tumor formation was detected. In conclusion, hPL-SHED emerges as a promising candidate for cell therapy, exhibiting considerable potential for clinical investigation.

Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting

Alzheimer’s disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades of research and clinical investigation. This might be partly due to a lack of widely available and cost-effective modalities for diagnosis and prognosis. Recently, the blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity and precision of the assays and measurement platforms. Several blood-based biomarkers have shown high potential for accurately detecting AD pathophysiology. As a result, there has been considerable interest in applying these biomarkers for diagnosis and prognosis, as surrogate metrics to investigate the impact of various covariates on AD pathophysiology and to accelerate AD therapeutic trials and monitor treatment effects. However, the lack of standardization of how blood samples and collected, processed, stored analyzed and reported can affect the reproducibility of these biomarker measurements, potentially hindering progress toward their widespread use in clinical and research settings. To help address these issues, we provide fundamental guidelines developed according to recent research findings on the impact of sample handling on blood biomarker measurements. These guidelines cover important considerations including study design, blood collection, blood processing, biobanking, biomarker measurement, and result reporting. Furthermore, the proposed guidelines include best practices for appropriate blood handling procedures for genetic and ribonucleic acid analyses. While we focus on the key blood-based AD biomarkers for the AT(N) criteria (e.g., amyloid-beta [Aβ]40, Aβ42, Aβ42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau and glial fibrillary acidic protein), we anticipate that these guidelines will generally be applicable to other types of blood biomarkers. We also anticipate that these guidelines will assist investigators in planning and executing biomarker research, enabling harmonization of sample handling to improve comparability across studies.

3D nerve proximity mapping of the medial branch of lumbar dorsal ramus: An anatomical study

ObjectiveLumbar medial branch (MB) radiofrequency ablation is a common intervention to treat facetogenic low back pain. Consensus among spine pain interventionalists is that the cannula tip should be placed adjacent to the periosteum of the lateral neck of the superior articular process (SAP) to ensure maximum contact with the MB. The spatial relationship of the nerve to the periosteum of the lateral neck of the SAP has not been quantified in 3D. The objectives of the current study were to: 1) use 3D modelling technology to quantify the location along the lateral neck of the SAP where the MB is in direct contact with the periosteum; and 2) identify target site(s) to optimize lumbar MB denervation. DesignSeventy lumbar dorsal rami in 14 formalin-embalmed specimens were dissected, digitized, and modeled in 3D. The 3D positional data of the MB were used to generate a novel nerve proximity map which provided a method to quantify and visualize the 3D course of the MB in relation to the periosteum of the lateral neck of SAP. The percent of the lateral neck of SAP in contact with the MB was quantified and consistent target site(s) identified. ResultsThere was variability in the percentage of the lateral neck of SAP in contact with the MB. The mean percentage of the lateral neck of SAP in contact with the MB for the L1-L5 levels ranged between 57.39 ± 10.72 % (for L1) to 81.54 ± 10.48 % (for L5). The nerve proximity map showed consistent course of the MB along the posterior portion of the lateral neck of SAP and at a novel target site distal to the mamillo-accessory notch (i.e. sub-mammillary landmark). ConclusionThe percent of the lateral neck that was in contact with the MB was quantified and visualized using a novel nerve proximity mapping methodology which may be used to inform cannula tip depth placement. Further, the nerve proximity maps were used to identify an alternative landmark to extend the length of the MB captured. The proposed sub-mammillary landmark may be a viable target site pending future anatomical and clinical investigations.

Vinpocetine alleviated alveolar epithelial cells injury in experimental pulmonary fibrosis by targeting PPAR-γ/NLRP3/NF-κB and TGF-β1/Smad2/3 pathways

This study aimed to investigate the potential anti-fibrotic activity of vinpocetine in an experimental model of pulmonary fibrosis by bleomycin and in the MRC-5 cell line. Pulmonary fibrosis was induced in BALB/c mice by oropharyngeal aspiration of a single dose of bleomycin (5 mg/kg). The remaining induced animals received a daily dose of pirfenidone (as a standard anti-fibrotic drug) (300 mg/kg/PO) and vinpocetine (20 mg/kg/PO) on day 7 of the induction till the end of the experiment (day 21). The results of the experiment revealed that vinpocetine managed to alleviate the fibrotic endpoints by statistically improving (P ≤ 0.05) the weight index, histopathological score, reduced expression of fibrotic-related proteins in immune-stained lung sections, as well as fibrotic markers measured in serum samples. It also alleviated tissue levels of oxidative stress and inflammatory and pro-fibrotic mediators significantly elevated in bleomycin-only induced animals (P ≤ 0.05). Vinpocetine managed to express a remarkable attenuating effect in pulmonary fibrosis both in vivo and in vitro either directly by interfering with the classical TGF-β1/Smad2/3 signaling pathway or indirectly by upregulating the expression of Nrf2 enhancing the antioxidant system, activating PPAR-γ and downregulating the NLRP3/NF-κB pathway making it a candidate for further clinical investigation in cases of pulmonary fibrosis.

Cardiac repolarization abnormalities and neurally mediated syncope: overlooked aspects in the diagnosis of pheochromocytoma

BackgroundPheochromocytoma is a rare catecholamine-producing tumour originating from adrenal chromaffin cells. Classic clinical presentation includes headache, diaphoresis and palpitation. Syncope is uncommon and may result from hypotension or arrhythmia. We report a case of neurally mediated syncope in pheochromocytoma associated with cardiac repolarization abnormalities, a unique presentation of the disease.Case presentationThis case report presents a 28 year-old woman, describing recurrent syncope usually preceded by prodromes such as headache, visual blurring, heart palpitations and psychomotor agitation. Firstly she was diagnosed with anxiety and depression, but there was no improvement of symptoms with psychiatric treatment. Previous Holter revealed long QT interval. Echocardiogram showed normal dimensions, preserved left ventricular function and no valvopathies. The patient was referred for a Head-up tilt test (HUTT) in order to investigate reflex syncope. The electrocardiogram (ECG) exhibited normal sinus rhythm and diffuse cardiac repolarisation abnormalities. HUTT was positive for vasodepressor type neurally mediated syncope and ECG showed U waves after a syncope episode. This electrocardiographic finding motivated further clinical investigation. The patient also described abdominal pain, increased abdominal volume, weight loss and blood pressure instability. Based on clinical history and ventricular repolarisation abnormalities uncovered by HUTT, pheochromocytoma was suspected. Urinary test was positive for catecholamines and the abdominal imaging revelead expansive lesion. She underwent surgery to remove the pheochromocytoma, confirmed by immunohistochemistry.ConclusionsAfter surgery she had no recurrency of symptoms, remaining asymptomatic after six years of follow-up, suggesting a cause-effect relationship between neurally mediated syncope and pheochromocytoma.

Role of angiotensin receptor-neprilysin inhibitor in diabetic complications.

Diabetes mellitus is a prevalent disorder with multi-system manifestations, causing a significant burden in terms of disability and deaths globally. Angio-tensin receptor-neprilysin inhibitor (ARNI) belongs to a class of medications for treating heart failure, with the benefits of reducing hospitalization rates and mortality. This review mainly focuses on the clinical and basic investigations related to ARNI and diabetic complications, discussing possible physiological and molecular mechanisms, with insights for future applications.

Hierarchical multinomial processing tree models for meta-analysis of diagnostic accuracy studies

Abstract Meta-analysis represents a widely accepted approach for evaluating the accuracy of diagnostic tools in clinical and psychological investigations. This article investigates the applicability of multinomial tree models recently suggested in the literature under a fixed-effects formulation for assessing the accuracy of binary classification tools, where the study specific disease prevalences are taken into account. The model proposed in this article extends previous results to a hierarchical structure accounting for the variability between the studies included in the meta-analysis. Interestingly, by exploiting the parameter separability of the complete likelihood function, the resulting hierarchical multinomial tree model is shown to coincide, in its interest parameter component, with the well-known bivariate random-effects model under an exact within-study distribution for the number of true positives and true negatives subjects. The proposal is in line with a latent-trait approach, where inference follows a frequentist point of view. The applicability of the proposed model and its performance with respect to its fixed-effects counterpart and to the approximate bivariate random-effects model based on normality assumptions commonly used in the literature is evaluated in a series of simulation studies. Methods are applied to a real meta-analysis about the accuracy of the confusion assessment method as delirium screening tool.

Reasons for Delay in Presentation of Acute Stroke Patients in Teritary Health Centre in Abuja

Background: Stroke is a life-threatening condition which continues to be a major public health problem leading to death and severe neurologic disability. The time of presentation remains a crucial for the use of intravenous thrombolysis. This study aims at evaluating the time to presentation of acute stroke and the factors that affect this time, and see if efforts could be made to reduce delay to enhance therapeutic intervention. Methods: This cross-sectional study was carried out with a total of eighty-two consecutive patient admitted into the medical wards. All patients had full clinical assessment and investigations, including demographic aspects, Prior and source of knowledge of stroke warning symptom, means of transportation to the hospital and duration before presentation and possible reasons for delay. Data collected was analysed by frequency, mean, standard deviation and chi-square test. Results: Of the 82 study participants, 50% had Cerebral infarction, 34.1% intracerebral hemorrhage, and 15.9% subarachnoid hemorrhage. Those with previous knowledge of one-sided weakness were 78% and difficulty with speech were 54.9% among the stroke warning symptoms. About 33% presented before 4 hours while 50% of patient presented between 6 to 11hours. Only 3.66% used ambulance service to the hospital. Among the possible reason for delay 45.1% were not aware of the dangers of delayed treatment and 40.2% complain of distance to the hospital. Conclusion: Our study though hospital-based, has been able to highlight unawareness of the dangers of delayed treatment and distance to the hospital as major factors contributing to prehospital delay which are obviously modifiable.

The role of color doppler in high risk pregnancies: A prospective comparative study

Pregnancy can be considered as the most beautiful period of a woman’s life. The recent medical advances are helpful in taking very good care of the female throughout her pregnancy. The pregnancy is constantly observed by clinical examination, laboratory investigations, and radiographic examinations at specific intervals throughout its course.To study the role of doppler ultrasound in high-risk pregnancies.This is a prospective comparative study was conducted in department of Obstetrics and Gynaecology at Government medical college, Nagpur. The study period was 12 months. 232 patients were included in this study.In our study, 2 patients had Chronic hypertension, 2 patients had GDM, 1 patient had Gestational hypertension, 3 patients had Anaemia, 6 patients had Heart Disease, 5 patients had HIV positive,15 patients had Hypothyroidism, 2 patients had Increased BP, 1 patient had Overt DM,6 patients had Pre-eclampsia,1 patient had previous abortion, 4 patients had Rh negative, 5 patients had Sickle Cell Disease(SS) and 15 patients had Sickle Cell trait(AS). Distribution of normal doppler changes in cases according to high risk factor was statistically significant (p<0.0001).In our study, NICU Admission with doppler changes was statistically significant and Association of Baby weight in cases according to doppler changes in uterine artery and Baby weight in cases according to doppler changes in umbilical artery was not statistically significant.

Central Serous Chorioretinopathy: Epidemiology, Genetics and Clinical Features.

Central serous chorioretinopathy (CSCR) is the fourth most common medical retinal disease. Moderate vision loss occurs in approximately one-third of patients who have the chronic form of the disease. CSCR has a multifactorial etiology, with acquired risk factors and increasing evidence of genetic susceptibility factors. The detection of new gene variants in CSCR and association of these variants with age-related macular degeneration provide insights into possible disease mechanisms. The contribution of multimodal ocular imaging and associated research studies to the modern-day clinical investigation of CSCR has been significant. This review aims to provide an overview of the most significant epidemiological and genetic studies of CSCR, in addition to describing its clinical and multimodal imaging features. The review also provides an update of the latest evidence from studies investigating pathophysiological mechanisms in CSCR and current opinions on multimodal imaging to better classify this complex retinal disease.

Advances in combined neuroendocrine carcinoma of lung cancer.

Lung cancer incidence and mortality rates are increasing worldwide, posing a significant public health challenge and an immense burden to affected families. Lung cancer encompasses distinct subtypes, namely, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). In clinical investigations, researchers have observed that neuroendocrine tumors can be classified into four types: typical carcinoid, atypical carcinoid, small-cell carcinoma, and large-cell neuroendocrine carcinoma based on their unique features. However, there exist combined forms of neuroendocrine cancer. This study focuses specifically on combined pulmonary carcinomas with a neuroendocrine component. In this comprehensive review article, the authors provide an overview of combined lung cancers and present two pathological images to visually depict these distinctive subtypes.

Genetically determined gut microbiota associates with pulmonary arterial hypertension: a Mendelian randomization study

BackgroundEmerging evidences have demonstrated that gut microbiota composition is associated with pulmonary arterial hypertension (PAH). However, the underlying causality between intestinal dysbiosis and PAH remains unresolved.MethodAn analysis using the two-sample Mendelian randomization (MR) approach was conducted to examine the potential causal relationship between gut microbiota and PAH. To assess exposure data, genetic variants associated with 196 bacterial traits were extracted from the MiBioGen consortium, which included a sample size of 18,340 individuals. As for the outcomes, summary statistics for PAH were obtained from the NHGRI-EBI GWAS Catalog, which conducted a meta-analysis of four independent studies comprising a total of 11,744 samples. Causal effects were estimated employing various methods, including inverse variance weighted (IVW), MR-Egger, weighted median, weight mode and simple mode, with sensitivity analyses also being implemented with Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots.ResultsFollowing false discovery rate (FDR) correction, the genetically predicted genus Eubacterium fissicatena group (odds ratio (OR) 1.471, 95% confidence interval (CI) 1.178–1.837, q = 0.076) exhibited a causal association with PAH. In addition, the genus LachnospiraceaeUCG004 (OR 1.511, 95% CI 1.048–2.177) and genus RuminococcaceaeUCG002 (OR 1.407, 95% CI 1.040–1.905) showed a suggestive increased risk of PAH, while genus Eubacterium eligens group (OR 0.563, 95% CI 0.344–0.922), genus Phascolarctobacterium (OR 0.692, 95% CI 0.487–0.982), genus Erysipelatoclostridium (OR 0.757, 95% CI 0.579–0.989) and genus T–yzzerella3 (OR 0.768, 95% CI 0.624–0.945) were found to have nominal protective effect against PAH.ConclusionThe findings from our MR study have revealed a potential causal relationship between gut microbiota and PAH. Specifically, we have identified four types of gut microbiota that exhibit a protective effect on PAH, as well as three types that have a detrimental impact on PAH, thereby offering valuable insights for future mechanistic and clinical investigations in the field of PAH.

Neuromyelitis optica spectrum disorders registry system in Iran: Validity of data sets

BackgroundA targeted structure for recording, monitoring, and follow-up of patients with neuromyelitis optica spectrum disorders (NMOSD) is in demand. To obtain the correct and uniform standardized information registry system, it is necessary to use a data set that has good validity to help policy-makers systematically plan for improvements in the quality of care. The main goal of the present study was to develop a NMOSD data set for the national registry system in Iran (NMORI) and to evaluate the validity of the presented data set. MethodsThe NMORI data set consisted of baseline characteristics, disease and exposure history, background and past medical history, diagnosis and treatment, clinical features, imaging, and para-clinical findings. The content validity was evaluated by 18 experts from Iran, Japan, and Denmark by scoring each of the questionnaire items in term of transparency, simplicity, and relevance. According to the points given, the content validity index (CVI) and content validity ratio (CVR) scores were calculated and compared with the critical limit. ResultsThe current study was designed as a 125-items data set which was considered valid. In terms of relevance 110 out of 125 items, simplicity 113 out of 125 items, and transparency 123 out of 125 items had Item-CVI>0.79. All Scale-level-CVI values were greater than 0.9, showing noticeable content validity. In this data set, 112 items had CVR > 0.49, which was considered an acceptable level of significance. ConclusionThe implementing of NMORI is important in a developing country such as Iran with significant increasing prevalence of this disease. This registry facilitates a uniform and valid diagnosis and is considered valid for clinical investigation and epidemiological research on NMOSD. Scientists and healthcare policymakers can rely on a validated data set in order to have access to accurate data.

Nephrotic Syndrome Throughout Childhood: Diagnosing Podocytopathies From the Womb to the Dorm.

The etiologies of podocyte dysfunction that lead to pediatric nephrotic syndrome (NS) are vast and vary with age at presentation. The discovery of numerous novel genetic podocytopathies and the evolution of diagnostic technologies has transformed the investigation of steroid-resistant NS while simultaneously promoting the replacement of traditional morphology-based disease classifications with a mechanistic approach. Podocytopathies associated with primary and secondary steroid-resistant NS manifest as diffuse mesangial sclerosis, minimal change disease, focal segmental glomerulosclerosis, and collapsing glomerulopathy. Molecular testing, once an ancillary option, has become a vital component of the clinical investigation and when paired with kidney biopsy findings, provides data that can optimize treatment and prognosis. This review focuses on the causes including selected monogenic defects, clinical phenotypes, histopathologic findings, and age-appropriate differential diagnoses of nephrotic syndrome in the pediatric population with an emphasis on podocytopathies.

Thyroid hormone analogues: Promising therapeutic avenues to improve the neurodevelopmental outcomes of intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is a pregnancy complication impairing fetal growth and development. The compromised development is often attributed to disruptions of oxygen and nutrient supply from the placenta, resulting in a number of unfavourable physiological outcomes with impaired brain and organ growth. IUGR is associated with compromised development of both grey and white matter, predisposing the infant to adverse neurodevelopmental outcomes, including long-lasting cognitive and motor difficulties. Cerebral thyroid hormone (TH) signalling, which plays a crucial role in regulating white and grey matter development, is dysregulated in IUGR, potentially contributing to the neurodevelopmental delays associated with this condition. Notably, one of the major TH transporters, monocarboxylate transporter-8 (MCT8), is deficient in the fetal IUGR brain. Currently, no effective treatment to prevent or reverse IUGR exists. Management strategies involve close antenatal monitoring, management of maternal risk factors if present and early delivery if IUGR is found to be severe or worsening in utero. The overall goal is to determine the most appropriate time for delivery, balancing the risks of preterm birth with further fetal compromise due to IUGR. Drug candidates have shown either adverse effects or little to no benefits in this vulnerable population, urging further preclinical and clinical investigation to establish effective therapies. In this review, we discuss the major neuropathology of IUGR driven by uteroplacental insufficiency and the concomitant long-term neurobehavioural impairments in individuals born IUGR. Importantly, we review the existing clinical and preclinical literature on cerebral TH signalling deficits, particularly the impaired expression of MCT8 and their correlation with IUGR. Lastly, we discuss the current evidence on MCT8-independent TH analogues which mimic the brain actions of THs by being metabolised in a similar manner as promising, albeit underappreciated approaches to promote grey and white matter development and improve the neurobehavioural outcomes following IUGR.

Quantitative analysis of therapeutic peptides by CZE using multiple sample injection in hydrodynamically closed separation system.

Therapeutic peptides have emerged as an innovative and promising class of therapeutic compounds in modern medicine. Synthetic peptide analogs triptorelin and lanreotide are known for their pronounced clinical versatility and potency. In this study, we present the development and validation of novel methods based on capillary zone electrophoresis performed in hydrodynamically closed system (HCS) and paired with ultraviolet detection and repeated injection sample introduction. To the best of our knowledge, we developed the first capillary electrophoresis-based method for the determination of lanreotide, and concurrently, the first HCS method for the determination of triptorelin. Maximal separation efficiency and signal intensity were achieved using background electrolytes composed of 50mM formic acid with the addition of 0.05% (v/v) methyl-hydroxyethyl cellulose. The proposed methods exhibit favorable performance characteristics, namely, calibration curve (r2 exceeding 0.99), low limits of detection (0.25µg/mL in a water matrix and 0.5µg/mL in synthetic urine), acceptable precision (relative standard deviation ranging from 2.2% to 9.6% for intraday repeatability and between 5.2% and 14.9% for interday reproducibility), and accuracy (relative errors falling within the 91.1%-107.8% range). The method for triptorelin determination was then used for its quantification in a commercially available drug dosage form (powder for injection) and in spiked synthetic urine samples. The developed methods were also evaluated according to the novel blue applicability grade index, revealing their superior applicability. The results collectively point out the potential of the proposed methods for both quality control and clinical investigations.

Surgical treatment of Nutcracker Syndrome

The objective of this paper is to report early and mid-term outcomes of the surgical treatment Nutcracker Syndrome (NCS) in a single-center prospective study. Between January 2019 and September 2023, five patients with symptomatic NCS were treated at our center using left renal vein caudal transposition on the inferior vena cava, conducted through a midline incision of approximately 12 cm and a transperitoneal technique. Patient characteristics, presentation, length of hospital stay, and complications were analyzed. All diagnoses were established after clinical evaluation, ultrasound scanning, and radiological investigations, which confirmed left renal vein compression between the aorta and the Superior Mesenteric Artery (SMA). The average operating time was 159 minutes, with an average blood loss of 205 mL. There was no need for blood transfusions. Intensive care stay was not required and there were no early complications. The mean length of stay was 3.5 days. At a mean follow-up of 18.8 months, one patient reported persistent hematuria, and therefore underwent a secondary procedure, which incorporated patch venoplasty using the great saphenous vein. In our experience, left renal vein transposition appears to be a safe and effective procedure for the surgical management of severe NCS.

A cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys

The growing disparity between the demand for transplants and the available donor supply, coupled with an aging donor population and increasing prevalence of chronic diseases, highlights the urgent need for the development of platforms enabling reconditioning, repair, and regeneration of deceased donor organs. This necessitates the ability to preserve metabolically active kidneys ex vivo for days. However, current kidney normothermic machine perfusion (NMP) approaches allow metabolic preservation only for hours. Here we show that human kidneys discarded for transplantation can be preserved in a metabolically active state up to 4 days when perfused with a cell-free perfusate supplemented with TCA cycle intermediates at subnormothermia (25 °C). Using spatially resolved isotope tracing we demonstrate preserved metabolic fluxes in the kidney microenvironment up to Day 4 of perfusion. Beyond Day 4, significant changes were observed in renal cell populations through spatial lipidomics, and increases in injury markers such as LDH, NGAL and oxidized lipids. Finally, we demonstrate that perfused kidneys maintain functional parameters up to Day 4. Collectively, these findings provide evidence that this approach enables metabolic and functional preservation of human kidneys over multiple days, establishing a solid foundation for future clinical investigations.

Chloroquine-induced DNA damage synergizes with DNA repair inhibitors causing cancer cell death.

Cancer is a global health problem accounting for nearly one in six deaths worldwide. Conventional treatments together with new therapies have increased survival to this devastating disease. However, the persistent challenges of treatment resistance and the limited therapeutic arsenal available for specific cancer types still make research in new therapeutic strategies an urgent need. Chloroquine was tested in combination with different drugs (Panobinostat, KU-57788 and NU-7026) in 8 human-derived cancer cells lines (colorectal: HCT116 and HT29; breast: MDA-MB-231 and HCC1937; glioblastoma: A-172 and LN-18; head and neck: CAL-33 and 32816). Drug´s effect on proliferation was tested by MTT assays and cell death was assessed by Anexin V-PI apoptosis assays. The presence of DNA double-strand breaks was analyzed by phospho-H2AX fluorescent staining. To measure homologous recombination efficiency the HR-GFP reporter was used, which allows flow cytometry-based detection of HR stimulated by I-SceI endonuclease-induced DSBs. The combination of chloroquine with any of the drugs employed displayed potent synergistic effects on apoptosis induction, with particularly pronounced efficacy observed in glioblastoma and head and neck cancer cell lines. We found that chloroquine produced DNA double strand breaks that depended on reactive oxygen species formation, whereas Panobinostat inhibited DNA double-strand breaks repair by homologous recombination. Cell death caused by chloroquine/Panobinostat combination were significantly reduced by N-Acetylcysteine, a reactive oxygen species scavenger, underscoring the pivotal role of DSB generation in CQ/LBH-induced lethality. Based on these data, we also explored the combination of CQ with KU-57788 and NU-7026, two inhibitors of the other main DSB repair pathway, nonhomologous end joining (NHEJ), and again synergistic effects on apoptosis induction were observed. Our data provide a rationale for the clinical investigation of CQ in combination with DSB inhibitors for the treatment of different solid tumors.