Common Cause Research Articles

A comparison of the phonation quotient between patients with voice disorders caused by benign vocal fold lesions and normal adults 20-80 years of age

Background: A voice evaluation is an important first step in analyzing voice symptoms and determining appropriate treatment plans. The phonation quotient is a valid aerodynamic parameter in voice evaluations which is an indirect source of information for evaluating the valve function of the vocal folds of patients with voice disorders, especially patients with voice disorders caused by tumors of the vocal folds which is the most common cause in the patients with voice disorders. Objective: The present study aims to determine and compare the phonation quotient between patients with voice disorders caused by benign vocal fold lesions and normal adults between 20-80 years of age. Materials and methods: The participants comprised 40 adults with voice disorders caused by benign vocal fold lesions and 40 with normal voices. All participants’ voices were evaluated in the Speech Clinic at Ramathibodi Hospital, Bangkok. The phonation quotient (PQ) was calculated by the ratio of vital capacity (VC) to the maximum phonation time (MPT). VC and MPT were measured using a phonatory aerodynamic system (PAS). Results: The results of the present study indicated that the mean value of the PQ of adults with normal voices was 122.60 cc/sec (SD=16.36). The mean value of the PQ of adults with voice disorders caused by benign vocal fold lesions was 292.08 cc/ sec (SD=97.14). The mean value of the PQ in the group with voice disorders caused by benign vocal fold lesions was significantly more significant than the mean value of the PQ in the group with normal voice. Conclusion: The significant difference between the phonation quotient of adults with voice disorders caused by benign vocal fold lesions and adults with normal voice was that the PQ might be an indicator for indirect evaluation of the airflow leakage related to the efficiency of vocal fold movement during phonation. The PQ can be the optional voice measurement for monitoring and analyzing the outcomes of voice therapy.

Arenobufagin inhibits lung metastasis of colorectal cancer by targeting c-MYC/Nrf2 axis

Colorectal cancer (CRC) is one of the commonest cancers worldwide. Metastasis is the most common cause of death in patients with CRC. Arenobufagin is an active component of bufadienolides, extracted from toad skin and parotid venom. Arenobufagin reportedly inhibits epithelial-to-mesenchymal transition (EMT) and metastasis in various cancers. However, the mechanism through which arenobufagin inhibits CRC metastasis remains unclear. This study aimed to elucidate the molecular mechanisms by which arenobufagin inhibits CRC metastasis. Wound-healing and transwell assays were used to assess the migration and invasion of CRC cells. The expression of nuclear factor erythroid-2-related factor 2 (Nrf2) in the CRC tissues was assessed using immunohistochemistry. The protein expression levels of c-MYC and Nrf2 were detected by immunoblotting. A mouse model of lung metastasis was used to study the effects of arenobufagin on CRC lung metastasis in vivo. Arenobufagin observably inhibited the migration and invasion of CRC cells by downregulating c-MYC and inactivating the Nrf2 signaling pathway. Pretreatment with the Nrf2 inhibitor brusatol markedly enhanced arenobufagin-mediated inhibition of migration and invasion, whereas pretreatment with the Nrf2 agonist tert‑butylhydroquinone significantly attenuated arenobufagin-mediated inhibition of migration and invasion of CRC cells. Furthermore, Nrf2 knockdown with short hairpin RNA enhanced the arenobufagin-induced inhibition of the migration and invasion of CRC cells. Importantly, c-MYC acts as an upstream modulator of Nrf2 in CRC cells. c-MYC knockdown markedly enhanced arenobufagin-mediated inhibition of the Nrf2 signaling pathway, cell migration, and invasion. Arenobufagin inhibited CRC lung metastasis in vivo. Together, these findings provide evidence that interruption of the c-MYC/Nrf2 signaling pathway is crucial for arenobufagin-inhibited cell metastasis in CRC. Collectively, our findings show that arenobufagin could be used as a potential anticancer agent against CRC metastasis. The arenobufagin-targeted c-MYC/Nrf2 signaling pathway may be a novel chemotherapeutic strategy for treating CRC.

New Insights into the Relationship between Nutrition and Neuroinflammation in Alzheimer's Disease: Preventive and Therapeutic Perspectives.

Neurodegenerative diseases are progressive brain disorders characterized by inexorable synaptic dysfunction and neuronal loss. Since the most consistent risk factor for developing neurodegenerative diseases is aging, the prevalence of these disorders is intended to increase with increasing life expectancy. Alzheimer's disease is the most common cause of neurodegenerative dementia, representing a significant medical, social, and economic burden worldwide. Despite growing research to reach an early diagnosis and optimal patient management, no disease-modifying therapies are currently available. Chronic neuroinflammation has been recognized as a crucial player in sustaining neurodegenerative processes, along with pathological deposition of misfolded proteins, including amyloid-β and tau protein. Modulating neuroinflammatory responses may be a promising therapeutic strategy in future clinical trials. Among factors that are able to regulate neuroinflammatory mechanisms, diet, and nutrients represent easily accessible and modifiable lifestyle components. Mediterranean diet and several nutrients, including polyphenols, vitamins, and omega-3 polyunsaturated fatty acids, can exert antioxidant and anti-inflammatory properties, impacting clinical manifestations, cognitive decline, and dementia. This review aims to provide an updated overview of the relationship between neuroinflammation, nutrition, gut microbiota, and neurodegeneration. We summarize the major studies exploring the effects of diet regimes on cognitive decline, primarily focusing on Alzheimer's disease dementia and the impact of these results on the design of ongoing clinical trials.

Acroparesthesias: An Overview.

Acroparesthesia is a symptom characterized by a subjective sensation, such as numbness, tingling, prickling, and reduced sensation, affecting the extremities (fingers and toes). Despite its frequency, data regarding its diagnostic approach and management are scarce. The etiological diagnosis of acroparesthesia is sometimes challenging since it can be due to abnormality anywhere along the sensory pathway from the peripheral nervous system to the cerebral cortex. Acroparesthesia can reveal several diseases. It can be associated with rheumatic complaints such as arthritis or myalgia. Further cautions are required when paresthesia is acute (within days) in onset, rapidly progressive, severe, asymmetric, proximal, multifocal, or associated with predominant motor signs (limb weakness) or severe dysautonomia. Acroparesthesia may reveal Guillain-Barré syndrome or vasculitis, requiring rapid management. Acroparesthesia is a predominant symptom of polyneuropathy, typically distal and symmetric, often due to diabetes. However, it can occur in other diseases such as vitamin B12 deficiency, monoclonal gammopathy of undetermined significance, or Fabry's disease. Mononeuropathy, mainly carpal tunnel syndrome, remains the most common cause of acroparesthesia. Ultrasonography contributes to the diagnosis of nerve entrapment neuropathy by showing nerve enlargement, hypoechogenic nerve, and intraneural vascularity. Besides, it can reveal its cause, such as space-occupying lesions, anatomical nerve variations, or anomalous muscle. Ultrasonography is also helpful for entrapment neuropathy treatment, such as ultrasound-guided steroid injection or carpal tunnel release. The management of acroparesthesia depends on its causes. This article aimed to review and summarize current knowledge on acroparesthesia and its causes. We also propose an algorithm for the management of acroparesthesia.

Revisiting the Role of B-RAF Kinase as a Therapeutic Target in Melanoma.

Malignant melanoma is the rarest but most aggressive and deadly skin cancer. Melanoma is the result of a malignant transformation of melanocytes, which leads to their uncontrolled proliferation. Mutations in the mitogen-activated protein kinase (MAPK) pathway, which are crucial for the control of cellular processes, such as apoptosis, division, growth, differentiation, and migration, are one of its most common causes. BRAF kinase, as one of the known targets of this pathway, has been known for many years as a prominent molecular target in melanoma therapy, and the following mini-review outlines the state-of-the-art knowledge regarding its structure, mutations and mechanisms.

Mild Thrombocytopenia, a Predictor of Outcomes After Laparoscopic Cholecystectomy: Assessment of Surgical Risk in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease.

A common cause of mild thrombocytopenia is chronic liver disease, the most common etiology being metabolic dysfunction-associated steatotic liver disease (MASLD). Mild thrombocytopenia is a well-defined, independent marker of hepatic fibrosis in patients with chronic liver disease. Currently, there is a paucity of information available to characterize perioperative risk in patients with MASLD; therefore, the characterization of perioperative morbidity is paramount. We used a platelet threshold of 150×10 9 as a surrogate for fibrosis in patients undergoing laparoscopic cholecystectomy to study its effect on perioperative complications and mortality. We queried the American College of Surgeons National Surgical Quality Improvement Program database for laparoscopic cholecystectomies occurring from 2005 through 2018. Demographic differences between patients with and without thrombocytopenia were evaluated using the t test or the χ 2 test, whereas adjusted and unadjusted differences in outcome risk were evaluated using log-binomial regression models. We identified 437,630 laparoscopic cholecystectomies of which 6.9% included patients with thrombocytopenia. Patients with thrombocytopenia were more often males, older, and with chronic disease. Patients with thrombocytopenia and higher Aspartate Aminotransferase to Platelet Ratio Index scores had 30-day mortality rates risk ratio of 5.3 (95% CI: 4.8-5.9), with higher complication rates risk ratio of 2.4 (95% CI: 2.3-2.5). The most frequent complications included the need for transfusion, renal, respiratory, and cardiac. Perioperatively, patients with mild thrombocytopenia undergoing laparoscopic cholecystectomy had higher mortality rates and complications compared with patients with normal platelet counts. Thrombocytopenia may be a promising, cost-effective tool to identify patients with MASLD and estimate perioperative risk, especially if used in high-risk populations.

Outcomes of surgically managed adult traumatic brachial plexus injuries in an upper-middle-income country

BackgroundTraumatic brachial plexus injuries (TBPIs) are debilitating and complex to treat. The last five decades have seen advances in surgical management, and consequently improved functional outcomes in patients with these injuries. There is limited data available describing the outcomes of surgically managed TBPIs within the South African context. This study aimed to identify the common causes of injury, injury characteristics, and functional outcomes of surgically managed patients with TBPIs. MethodsWe conducted a retrospective chart review of all adult patients that underwent surgery for TBPIs over a period of ten years at a specialised hand unit in South Africa. The minimum follow-up period was one year. Patient demographic details, injury characteristics and functional outcomes were collected. Statistical analysis was performed to determine factors associated with functional outcomes. A good functional outcome for recovery was defined as a Medical Research Council (MRC) grade of three or more for the affected elements of the plexus at the most recent follow-up. ResultsForty-seven patients of median age 32 years were included in the final analysis. Most patients were male (87.2 %). The majority of patients were injured in motor vehicle accidents (MVAs) or from penetrating stab wounds (48.9 % and 38.3 % respectively). The median pre-operative MRC grade of the affected elements of the brachial plexus was 0.0, and post-operatively was 2.0. Fourteen patients (14 of 47, 29.8 %) had a good outcome and 33 had a poor outcome (33 of 47, 70.2 %). There was no difference in outcome comparing penetrating injury mechanisms to closed traction or blunt injuries, (p = 0.386, OR 1.75, 95 % CI 0.49–6.20). All patients with pan-plexal injuries had a poor outcome (15 of 33, 46 %). All patients who received intercostal (6 of 33, 18 %) or phrenic nerve transfers (3 of 33, 9 %) had a poor outcome. ConclusionAdult traumatic BPIs in this South African sample typically presented more than two months after injury and were comprised of a high proportion of penetrating injuries. Just under a third of surgically managed patients had a good outcome. Pan plexal injuries have uniformly poor outcomes. We recommend early referral for all TBPIs to a unit that manages BPI to improve outcomes.

Leveraging Directed Causal Discovery to Detect Latent Common Causes in Cause-Effect Pairs.

The discovery of causal relationships is a fundamental problem in science and medicine. In recent years, many elegant approaches to discovering causal relationships between two variables from observational data have been proposed. However, most of these deal only with purely directed causal relationships and cannot detect latent common causes. Here, we devise a general heuristic which takes a causal discovery algorithm that can only distinguish purely directed causal relations and modifies it to also detect latent common causes. We apply our method to two directed causal discovery algorithms, the information geometric causal inference (IGCI) of (Daniusis et al., 2010) and the kernel conditional deviance for causal inference of (Mitrovic et al., 2018), and extensively test on synthetic data-detecting latent common causes in additive, multiplicative and complex noise regimes-and on real data, where we are able to detect known common causes. In addition to detecting latent common causes, our experiments demonstrate that both the modified algorithms preserve the performance of the original in distinguishing directed causal relations.

Airway management during a respiratory arrest in a clinical simulation scenario. Experience at a pediatric residency program.

Introduction. Respiratory failure is the most common cause of cardiac arrest in pediatrics. Recognizing and managing it adequately is critical. Simulation is used to improve medical skills. The objective of this study was to establish the proportion of pediatric residents who recognized a respiratory arrest in a child at a simulation center. Methods. This was an observational study in 77 residents. A simulation of a patient with respiratory distress that progressed to respiratory arrest was used. Results. Among the 77 participants, 48 recognized respiratory arrest (62.3%). The mean time to recognize respiratory arrest was 38.16 seconds. Conclusion. Respiratory arrest was recognized by 62.3% of participants. Among those who did so, the average time was 38.16 seconds. Severe failures were noted in some of the expected interventions.

الكشف عن بعض عوامل الضراوة بين المبيضات المعزولة من المرضى وانتشار جين candidalysin ECE1

المبيضات البيضاء هي مسبب شائع لعدوى الجهاز التنفسي وداء المبيضات الفموي لدى الناس ، ومسببات أمراض الخميرة الانتهازية والأسباب الرئيسية للمرض والوفيات لدى الأشخاص الذين يعانون من نقص المناعة وتسبب التهابات سطحية على الأسطح المخاطية التي تصيب ملايين الأشخاص في جميع أنحاء العالم.  كان الهدف الرئيسي من هذه الدراسة هو التحقق من انتشار بعض عوامل الضراوة التي لها القدرة على تكوين الأغشية الحيوية (Biofilm)، والبروتينيز  (Proteinase)، وإنتاج الهيمولايسين( Hymolysine) بين  عزلات  C. albicans التي تشمل انتشار جين Candidalysin (ECE1).  تم جمع العينات خلال الفترة من ايار 2022 الى اب 2022  من 280 عينة (مسحة) لمرضى عراقيين  من مختلف الاعمار والاجناس غير مكررين  كانوا يعانون من داء المبيضات الفموي وامراض الجهاز التنفسي في مستشفيات بغداد (مستشفى مدينه الطب و مستشفى اليرموك التعليمي ومستشفى مدينه الامامين الطبية التعليمية).  تم زراعة العينات التي تم جمعها على وسط اكار  السابرويد  دكستروز (SDA) مضاف اليه كلورامفينيكول كمضاد للبكتيريا بتركيز 10 ميكجم / مل ، وتم حضن الاطباق الملقحة على وسط SDA عند 37 درجة مئوية لمدة تتراوح بين 24-48 ساعة.أظهرت نتائج الاستنبات أن 102 عينة كانت موجبه، منها58 (56.86%) من تجويف الفم و 44 (43.14%) من الجهاز التنفسي،  بينما 178 منها كانت سالبة , تم الكشف عن عزلات المبيضات باستخدام الطرق التقليدية والتي تشمل (النمو على وسط HiCrome Candida ، إنتاج الأنبوب الجرثومي Germ tube ، تكوين الابواغ الكلاميديه Clamydospore   وتم تأكيد نتئج التعريف باستخدام نضام VITEK-2  بينت النتائج ان من بين 102 عزلة C. albicans هي الاكثر شيوعا بين الانواع بنسبة 68.63 % ثم تلتها C. tropicalis  بنسبة %10.78  ثم C. kruzei %5.88  وC. kefyr %5.88 C. parapsilosis % 4.9  بينما كانت C. glabrata %  3.9  وتمثل النسبة الاقل بين الانواع . تم فحص حساسية عزلات المبيضات للأدوية المضادة للفطريات بطريقة انتشار القرص ، والتي أجريت على النحو الموصى به بواسطة(CLSI) M44-A -وثيقة  . أظهرت العزلات درجة عالية من الحساسية للأمفوتريسين-ب 93.14%    وكلوتريمازول 90.20% ونسياتين 85.92% ،تم التحقق من انتشار جينCandidalysin (ECE1)  بين 70 عزلة من C. albicans باستخدام تقنية تفاعل البلمرة المتسلسل  PCR  ، وأظهرت النتائج أن 41  58.57%  تحتوي على جين Ece1 في تجويف الفم والجهاز التنفسي. و 34 عزلة  48.57%  من C. albicans كانت منتجة قوية للغشاء الحيوي,  بينما 30 عزلة 42.86%  عزلة انتجت بروتيناز و 20 عزلة  28.57%  عزلة لديها القدرة على تحلل الدم.

Diagnostic Imaging for Retinoblastoma Cancer Staging: Guide for Providing Essential Insights for Ophthalmologists and Oncologists.

Retinoblastoma is the most common cause of all intraocular pediatric malignancies. It is caused by the loss of RB1 tumor suppressor gene function, although some tumors occur due to MYCN oncogene amplification with normal RB1 genes. Nearly half of all retinoblastomas occur due to a hereditary germline RB1 pathogenic variant, most of which manifest with bilateral tumors. This germline RB1 mutation also predisposes to intracranial midline embryonal tumors. Accurate staging of retinoblastoma is crucial in providing optimal vision-, eye-, and life-saving treatment. The AJCC Cancer Staging Manual has undergone significant changes, resulting in a universally accepted system with a multidisciplinary approach for managing retinoblastoma. The authors discuss the role of MRI and other diagnostic imaging techniques in the pretreatment assessment and staging of retinoblastoma. A thorough overview of the prevailing imaging standards and evidence-based perspectives on the benefits and drawbacks of these techniques is provided. Published under a CC BY 4.0 license. Test Your Knowledge questions for this article are available in the supplemental material.

Risk Factors and Frequency of Foot Ulceration in Patients Receiving Chronic Hemodialysis Treatment.

To determine the prevalence and risk factors of foot ulceration in patients receiving hemodialysis treatment. A total of 180 patients who received hemodialysis treatment in two state hospitals and a private health center between April 2017 and September 2017 were included in the study. The researchers collected data using a patient information form and by conducting physical evaluation of the lower extremities. They used the diabetic foot risk assessment algorithm to classify risk according to the data obtained. Of the patients receiving hemodialysis treatment, 6.7% had foot ulceration, 19.4% had a history of foot ulceration, and 8.3% had a history of hospitalization associated with ulceration in a lower extremity. Infected foot ulceration was the most common (6.1%) cause of hospitalizations. In the group with current or past foot ulceration, diabetic nephropathy was the most common etiologic factor of end-stage kidney disease (48.6%); there was a significant between-group difference in diabetic nephropathy (P < .05). Etiologic factors had a significant effect on foot ulcerations: As determined by univariate logistic regression, diabetes (odds ratio [OR], 2.727; P < .05), presence of neuropathy (OR, 4.208; P < .05), low-density lipoprotein cholesterol (OR, 1.013; P < .05), and serum albumin (OR, 0.302; P < .036) all had a statistically significant effect on the presence of foot ulcerations. Patients receiving hemodialysis treatment are at high risk for foot ulceration. Therefore, patient awareness strategies should be expanded to include individuals with end-stage renal disease regardless of diabetes status. Clinical and dialysis nurses should educate these patients about foot ulcerations and foot health to prevent ulcer development.

Torsion and clinical features in patients with acquired fourth cranial nerve palsy

This retrospective study aimed to compare objective/subjective torsion and other clinical characteristics of patients with acquired trochlear nerve palsy. This study included 82 consecutive patients who were diagnosed with acquired fourth cranial nerve palsy between 2014 and 2021 and who were followed up for ≥ 6 months. The etiologies, ocular deviation, objective and subjective torsions were reviewed. The etiologies were classified as ischemic, traumatic, brain lesion, idiopathic, or other. The patients were classified into two groups according to the recovery state: full recovery and partial/no-recovery. We compared the torsion and clinical features based on the etiology and recovery state. The average age was 59.1 ± 11.1 years, and 58 (71.0%) of the patients were male. The most common cause was ischemic (n = 49, 59.7%) and other common causes included traumatic (n = 16, 19.5%), brain lesion (n = 8, 9.8%), idiopathic (n = 5, 6.1%) and others (n = 4, 4.9%). Of the 82 patients, 56 (68.3%) were assigned to the full recovery group, and 26 (31.7%) were assigned to the partial/no-recovery group. The average age and number of patients with ischemic causes of palsy were greater in the full recovery group (p = 0.026 and p < 0.000, respectively). The vertical deviation angle, tilted angle on the Lancaster red-green test (LRGT), proportion of patients who experienced subjective torsion on the LRGT, and head tilt were smaller in the full recovery group (p = 0.037, 0.042, 0.045, and 0.006, respectively). Ischemic trochlear nerve palsy, advanced age, a small deviation angle at the primary position, and few cases of excyclotorsion on LRGT were characteristic of the full recovery group of acquired unilateral trochlear nerve palsy patients.

Profile of Blood Donors and Reasons for Deferral at a District Hospital in North Goa

Introduction: A blood transfusion is a life-sustaining procedure in several medical and surgical conditions. It isvital that an adequate inventory of safe blood is established by implementing stringent donor selection criteria andscreening for transfusion transmitted infections by ultrasensitive methods of detection. Despite a huge population,scarcity of blood lingers nationwide and it is important to analyse the varied reasons of deferrals in order to lessenthe deferrals in the future.The aim of this paper is to scrutinise the demographic profile of blood donors and evaluate the patterns andreasons for donor deferral at North Goa District hospital, India.Materials and Methods: This is a retrospective study carried out at the Blood Centre , North Goa Districthospital,India,. All those who registered for donation between June 2022 till May 2023 were included in the study.The donors were screened by a questionnaire followed by medical examination and were selected or deferredbased on the guidelines laid down by Drugs and Cosmetics Act,1940 and Directorate General of Health Services,MoHFW,Govt of India1.2 .Data was collected using a proforma and analysed by SPSS software wherever indicated.Results: During this time period, 2611 donors registered for blood donation, out of which 425 donors were deferreddue to diverse reasons. Most of the donors were voluntary donors(98.3%) of which majority were males(86.4%).The commonest cause of deferral in males was high BP(24%) and high Hb(11.3%) whereas the commonest cause ofdeferrals in females was low Hb (46.9%). Most of the donors were rejected due to temporary reasons(97.1%). Thecommonest reason of permanent deferrals was a medical history of uncontrolled DM.

A study to untangle the puzzle of urinary incontinence and frailty co-occurrence among older adults: The roles of depression and activity engagement.

To explore the co-occurrence of urinary incontinence and frailty by testing the roles of depression and activity engagement guided by the mechanisms of common cause and interaction pathways. A secondary analysis of a 1-year three-wave panel data collected from older nursing home residents in China. Changes in depression and activity engagement were regressed on urinary incontinence and frailty incidence underpinned by the common cause mechanism of chronic conditions co-occurrence, and these changes were also taken as mediators linking from frailty to urinary incontinence incidence supported by the interaction pathways' mechanism. A total of 348 older adults were included in this study, and 55.7% were women. The co-occurrence of urinary incontinence and frailty was found in 16.7% of the participants at baseline. Older adults with sole frailty at baseline had almost twice the rate of incident urinary incontinence (32.7%) compared with those without (16.7%) over a 1-year period. The subsample analyses showed that changes in depression and activity engagement failed to significantly predict the incidence of urinary incontinence and frailty. The mediating roles of these changes linking frailty to urinary incontinence incidence were also not statistically significant. The co-occurrence of urinary incontinence and frailty is prevalent in older nursing home residents. Older adults with frailty at baseline are more likely to develop urinary incontinence a year later. The common cause and interaction pathways mechanisms for the co-occurrence of urinary incontinence and frailty were not verified with changes in depression and activity engagement. The phenomenon of urinary incontinence and frailty co-occurrence should be given extreme emphasis. Although statistically significant findings on the roles of depression and activity engagement were not inferred, this study provides multiple possibilities for future studies to test and depict a clear picture of this co-occurrence. What problem did the study address? This study was designed to test the roles of depression and activity engagement in predicting the incidence of urinary incontinence and frailty, and the mediating roles in linking frailty to urinary incontinence incidence. What were the main findings? Despite the methodological pitfalls in literature have been addressed, neither depression nor activity engagement would significantly predict the incidence of urinary incontinence and frailty in older adults. Their mediating roles in linking frailty to urinary incontinence incidence were also not significant. Where and on whom will the research have an impact? Our findings add important pieces of evidence to promote researchers' understanding and provide an important basis for untangling the puzzle of urinary incontinence and frailty co-occurrence. The report of this study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement guidelines. No patient or public contribution.

Alzheimer's Disease: A Suitable Case for Treatment with Precision Medicine?

Alzheimer's disease (AD) is the most common cause of neurodegenerative impairment in elderly people. Clinical characteristics include short-term memory loss, confusion, hallucination, agitation, and behavioural disturbance. Owing to evolving research in biomarkers AD can be discovered at early onset, but the disease is currently considered a continuum, which suggests that pharmacotherapy is most efficacious in the preclinical phase, possibly 15 - 20 years before discernible onset. Present developments in AD therapy aim to respond to this understanding and go beyond the drug families that relieve clinical symptoms. Another important factor in this development is the emergence of precision medicine that aims to tailor treatment to specific patients or patient subgroups. This relatively new platform would categorize AD patients on the basis of parameters like clinical aspects, brain imaging, genetic profiling, clinical genetics and epidemiological factors. This review enlarges on recent progress in the design and clinical use of antisense molecules, antibodies, antioxidants, small molecules and gene editing to stop AD progress and possibly reverse the disease on the basis of relevant biomarkers.

Abstract 6145: A trans-ethnic meta-analysis identified additional novel genomic loci associated with cervical cancer

Abstract Introduction: Cervical cancer is the second most common cause of cancer-related deaths among women worldwide. Genome-wide association studies (GWAS) have identified genetic variants associated with cervical cancer. However, these discoveries have been limited by the small sample sizes of the individual cohorts. To identify additional novel loci associated with cervical cancer, we performed a trans-ethnic meta-analysis. Methods: GWAS summary data for trans-ethic meta-analysis were identified in women of European ancestry from the UK Biobank, East Asian ancestry from Biobank Japan, and African ancestries from the pan-UK Biobank and Johannesburg cancer study. Meta-analyses were performed using fixed effect inverse variance weighted method implemented in GWAMA. To localize putative genomic loci associated with cervical cancer, we performed fine mapping using the Bayesian approach by calculating the marginal posterior probability of causality for each single nucleotide polymorphisms (SNPs) and 99% credible set size. Results: Our meta-analysis identified four additional novel genomic loci associated with cervical cancer. These loci include: rs147778467 (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.08-1.16, P-value = 3.12 x 10-08) in RGS21, rs53150478 (OR =1.03, 95%CI = 1.01-1.05, P-value = 4.48 x 10-08) in MAN1C1, rs113842373 (OR = 0.68, 95%CI = 0.56-0.81, P-value = 2.31 x 10-09) in LINCO1850 and rs75372437 (OR = 0.80, 95%CI = 0.72-0.88, P-value = 3.32 x 10-08) in RNU6-356P. These loci are implicated in carcinogenic pathways. Moreover, our Bayesian fine mapping identified five loci with a marginal posterior probability of causality &amp;gt; 1 and reduced the 99% credible set sizes. Conclusion: We identified additional novel loci associated with cervical cancer and our fine mapping identified loci with a high posterior probability of being causal. Citation Format: Abram Bunya Kamiza, Jean-Tristan Brandenburg, Michele Ramsay, Christopher Mathew. A trans-ethnic meta-analysis identified additional novel genomic loci associated with cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6145.

Neoplasia detection in FIT positive screening colonoscopies compared with an age-controlled symptomatic cohort: a retrospective review

Colonoscopy following a positive FIT test in an average risk population is effective in reducing CRC incidence and mortality. While lower gastrointestinal symptoms remain a common cause for referral for colonoscopy, symptoms are poor predictors of clinically significant disease. The study was performed to compare neoplasia detection FIT +ve individuals and age-matched symptomatic cohorts. A single centre retrospective observational study was performed including all index colonoscopies performed on patients aged 60-70 from January 2015 to September 2021. Diagnostic yield was reported as adenoma detection rate, SSL detection rate, detection of high risk finding or adenocarcinoma. 8,106 colonoscopies were performed on patients aged 60-70 years. 3,695 (45.6%) originated from screening (FIT +ve). With exclusion criteria applied, 2,640 (59.9%) for screening and 1,767 (40.1%) for symptomatic patients were included. Median age in screening was 65 years (IQR 62-67) and 64 years in the symptomatic group (IQR 62-68), with male predominance in both groups (n=1,536, 58.1%, n=944, 53.4%). There were significant differences in both the ADR (56% vs 26.3%, p&amp;lt;0.01) and the SSLDR (10.4% vs. 8.1%, p=0.05) in the screening cohort compared to the symptomatic group. High risk findings (21.3% vs. 7.5%, p&amp;lt;0.01) were significantly more prevalent in the screening group with a considerably higher colorectal cancer (4.7% vs. 0.9%, p=&amp;lt;0.001) detection rate. FIT based triage significantly outperforms symptom based investigation for individuals in the 60-70 age group. Patients should be preferentially referred to organised colorectal cancer screening. FIT can be performed on symptomatic patients, to identify low risk individuals.

Abstract 3211: Development of first in class zip code drug conjugate in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PC) is the fourth most common cancer-related cause of death in Western countries. It is projected that PC will become the second most prevalent cause of cancer-related mortality by the year 2030. Although chemotherapy may offer certain advantages to those who have been diagnosed with pancreatic cancer, its effectiveness is notably constrained by the emergence of chemoresistance and excessive toxicity. In recent studies, it has been established that circulating tumor DNA (ctDNA) serves as a mechanism for cell-specific genetic transfer. We discovered that transposon sequences (known as Zip Codes, ZC) were responsible for ctDNA cell targeting. Therefore, we investigated the possibility of hijacking these ZC to deliver drugs specifically. We began by determining whether PDCA ZC synthesized chemically could target PDCA cells selectively. To achieve this, ZC sequences were labeled with CY5 for high-throughput microscopy. Results show that numerous PDCA-ZC were specific and efficient at targeting PC cell lines while sparing other cancer cell lines. The AluSc8 (PCZC) sequence was chosen for further investigation. The specificity of PCZC for targeting cells was validated using pancreatic islet cells. Based on these findings, we developed a technique for conjugating PCZC with SN38 via a CL2A linker. The results indicated that PCZC-SN38 was a very effective agent at killing PC cells (IC50: 1 μg), but not other cancer cell lines. The therapeutic efficacy of PCZC-N38 was evaluated in vivo using PDX (patient-derived xenografts, Garcia et al Plos One 2013). Maximum tolerated dose testing (MTD) (dosing from 1 to 21 mg of PCZC-SN38/Kg) failed to reach an MTD. Subsequently, we evaluated the efficacy signal of PCZC-SN38 by administering PCZC-SN38 to animals three times per week for three weeks at concentrations of 3 and 30 mg/kg of DNA (equivalent to 0.05 and 0.5 SN38 mg/kg). We used animals treated with vehicle, PCZC alone, and irinotecan (either once per week (50 mg/kg) or three times per week (0.5 mg/Kg) as a comparison. PCZC-SN38 decreased tumor growth by 41% and 70%, respectively, when compared to the vehicle or PCZC alone. The observed efficacy did not result in a change in body weight. In contrast, every animal administered irinotecan at a dosage of 50 mg/kg died within a week. On the contrary, animals that were given irinotecan at a dosage of 0.5 mg/kg demonstrated a growth inhibition of 60% and exhibited remarkable tolerability. Currently, research is being undertaken to determine the therapeutic efficacy of PCZC-SN38 at higher doses. The results outlined in this study illustrate the preliminary application of PC targeted drug delivery using a PC zip code drug conjugate. The results of our study demonstrate an innovative methodology for targeting PC cells specifically with therapeutic cargo material and supports further preclinical development of PCZC-SN38 for PC. Citation Format: Munnever Cinar, Purnachandra Ganji, Andrey Pisarev, Lourdes Martinez-Medina, Dhana S. Bandi, Pavan K. Puvvula, Steven Chang, Daniel Maneval, Bassel El-Rayes, Leon Bernal-Mizrachi. Development of first in class zip code drug conjugate in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3211.

Breastfeeding and fatty liver - is there any association?

The campaign to promote the natural feeding of infants, at least for the first six months of life, conducted over recent years has deep justification from a medical point of view. Numerous gynecological and pediatric societies around the world recommend breastfeeding as the most appropriate way of feeding infants. It has been proven that the benefits of this type of nutrition go beyond nutritional aspects, proper growth and development. The list of long-term metabolic benefits, which include reducing the incidence of obesity, allergies, infections and diabetes, is constantly growing. It has been shown that the method of feeding infants using various mechanisms may influence the tendency of the liver to accumulate fatty compounds and develop fatty liver disease with its metabolic consequences leading to liver failure, cirrhosis and hepatocellular carcinoma. This is an important discovery due to the growing obesity epidemic in adults and children. Metabolic dysfunction - associated fatty liver disease (MAFLD) has become the most common cause of chronic liver disease, affecting 25% of the global population. The results of studies conducted in recent years have shown the protective effect of breastfeeding on the risk of developing MAFLD later in life in both children and breastfeeding women. New scientific reports provide the basis for qualifying breastfeeding as a modifiable risk factor for MAFLD.