Pub Date : 2023-12-29eCollection Date: 2023-12-01DOI: 10.59249/TDBJ7410
Prerana R Chowdhury, Shamala Salvamani, Baskaran Gunasekaran, Hoh B Peng, Vaidehi Ulaganathan
Colorectal cancer (CRC) has been recorded amongst the most common cancers in the world, with high morbidity and mortality rates, and relatively low survival rates. With risk factors such as chronic illness, age, and lifestyle associated with the development of CRC, the incidence of CRC is increasing each year. Thus, the discovery of novel biomarkers to improve the diagnosis and prognosis of CRC has become beneficial. Long non-coding RNAs (lncRNAs) have been emerging as potential players in several tumor types, one among them is the lncRNA H19. The paternally imprinted oncofetal gene is expressed in the embryo, downregulated at birth, and reappears in tumors. H19 aids in CRC cell growth, proliferation, invasion, and metastasis via various mechanisms of action, significantly through the lncRNA-microRNA (miRNA)-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network, where H19 behaves as a miRNA sponge. The RNA transcript of H19 obtained from the first exon of the H19 gene, miRNA-675 also promotes CRC carcinogenesis. Overexpression of H19 in malignant tissues compared to adjacent non-malignant tissues marks H19 as an independent prognostic marker in CRC. Besides its prognostic value, H19 serves as a promising target for therapy in CRC treatment.
{"title":"H19: An Oncogenic Long Non-coding RNA in Colorectal Cancer.","authors":"Prerana R Chowdhury, Shamala Salvamani, Baskaran Gunasekaran, Hoh B Peng, Vaidehi Ulaganathan","doi":"10.59249/TDBJ7410","DOIUrl":"10.59249/TDBJ7410","url":null,"abstract":"<p><p>Colorectal cancer (CRC) has been recorded amongst the most common cancers in the world, with high morbidity and mortality rates, and relatively low survival rates. With risk factors such as chronic illness, age, and lifestyle associated with the development of CRC, the incidence of CRC is increasing each year. Thus, the discovery of novel biomarkers to improve the diagnosis and prognosis of CRC has become beneficial. Long non-coding RNAs (lncRNAs) have been emerging as potential players in several tumor types, one among them is the lncRNA H19. The paternally imprinted oncofetal gene is expressed in the embryo, downregulated at birth, and reappears in tumors. H19 aids in CRC cell growth, proliferation, invasion, and metastasis via various mechanisms of action, significantly through the lncRNA-microRNA (miRNA)-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network, where H19 behaves as a miRNA sponge. The RNA transcript of H19 obtained from the first exon of the H19 gene, miRNA-675 also promotes CRC carcinogenesis. Overexpression of H19 in malignant tissues compared to adjacent non-malignant tissues marks H19 as an independent prognostic marker in CRC. Besides its prognostic value, H19 serves as a promising target for therapy in CRC treatment.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139075610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-29eCollection Date: 2023-12-01DOI: 10.59249/PAEJ4854
Prince B Vaghela, Archana M Navale, Chirangi B Patel, Nishant H Patidar, Prachi D Nahar, Farmi Patel, Zainab Pathan, Barsha Kumari
Objectives: The aim of this study was to investigate whether chia (Salvia hispanica) seeds, which are rich in omega-3 fatty acids, amino acids, and vitamins with antioxidant properties, can mitigate the negative effects on male reproductive function caused by cyclophosphamide, a frequently used chemotherapeutic agent. Methods: Male wistar rats are divided into seven groups (n=6). All groups except the normal control (NC) received cyclophosphamide (30mg/kg, i.p.) for the first 5 days. The standard group received clomiphene citrate (0.25 mg/kg, p.o.). Treatment groups T1%, T5%, T10%, and ω-3 received 1%, 5%, and 10% chia seeds in the diet, and 880 mg/kg omega-3 fatty acid (p.o) respectively for 15 days. The effect on the reproductive system was evaluated by analysis of epididymal sperm characteristics, biochemical parameters, and serum testosterone level. Results: Clomiphene citrate improved oligospermia via hormone mediated effect. Chia seeds and omega-3 fatty acid treatment also showed improvement in reproductive parameters including oxidative stress and histological features of the testes. Omega-3 fatty acid treatment was more effective for the prevention of cyclophosphamide toxicity on testes as compared to chia seeds. Nasal bleeding was noted in several animals subjected to chia seed treatment. This occurrence might be attributed to chia seeds' impact on coagulation and/or platelet function, potentially heightened due to chemotherapy associated bone marrow suppression. Conclusions: In our study, chia seeds as well as omega-3 fatty acid treatment were found to be protective against cyclophosphamide-induced reproductive toxicity in rats. However, the adverse effect of hemorrhage associated with drug interaction of chia seeds with cytotoxic chemotherapeutic drugs needs careful attention and further investigation.
{"title":"Protective Effects of Chia Seeds and Omega-3 Fatty Acid against Cyclophosphamide-Induced Oligospermia in Male Wistar Rats: Potential Risks of Adverse Drug Interaction with Chia Seeds.","authors":"Prince B Vaghela, Archana M Navale, Chirangi B Patel, Nishant H Patidar, Prachi D Nahar, Farmi Patel, Zainab Pathan, Barsha Kumari","doi":"10.59249/PAEJ4854","DOIUrl":"10.59249/PAEJ4854","url":null,"abstract":"<p><p><b>Objectives</b>: The aim of this study was to investigate whether chia (<i>Salvia hispanica</i>) seeds, which are rich in omega-3 fatty acids, amino acids, and vitamins with antioxidant properties, can mitigate the negative effects on male reproductive function caused by cyclophosphamide, a frequently used chemotherapeutic agent. <b>Methods</b>: Male wistar rats are divided into seven groups (n=6). All groups except the normal control (NC) received cyclophosphamide (30mg/kg, i.p.) for the first 5 days. The standard group received clomiphene citrate (0.25 mg/kg, p.o.). Treatment groups T1%, T5%, T10%, and ω-3 received 1%, 5%, and 10% chia seeds in the diet, and 880 mg/kg omega-3 fatty acid (p.o) respectively for 15 days. The effect on the reproductive system was evaluated by analysis of epididymal sperm characteristics, biochemical parameters, and serum testosterone level. <b>Results</b>: Clomiphene citrate improved oligospermia via hormone mediated effect. Chia seeds and omega-3 fatty acid treatment also showed improvement in reproductive parameters including oxidative stress and histological features of the testes. Omega-3 fatty acid treatment was more effective for the prevention of cyclophosphamide toxicity on testes as compared to chia seeds. Nasal bleeding was noted in several animals subjected to chia seed treatment. This occurrence might be attributed to chia seeds' impact on coagulation and/or platelet function, potentially heightened due to chemotherapy associated bone marrow suppression. <b>Conclusions</b>: In our study, chia seeds as well as omega-3 fatty acid treatment were found to be protective against cyclophosphamide-induced reproductive toxicity in rats. However, the adverse effect of hemorrhage associated with drug interaction of chia seeds with cytotoxic chemotherapeutic drugs needs careful attention and further investigation.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139075613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-29eCollection Date: 2023-12-01DOI: 10.59249/VHYE2306
Yi Zhen Hor, Shamala Salvamani, Baskaran Gunasekaran, Koh Rhun Yian
Colorectal Neoplasia Differentially Expressed (CRNDE), a long non-coding RNA that was initially identified as aberrantly expressed in colorectal cancer (CRC) has also been observed to exhibit elevated expression in various other human malignancies. Recent research has accumulated substantial evidence implicating CRNDE as an oncogenic player, exerting influence over critical cellular processes linked to cancer progression. Particularly, its regulatory interactions with microRNAs and proteins have been shown to modulate pathways that contribute to carcinogenesis and tumorigenesis. This review will comprehensively outline the roles of CRNDE in colorectal, liver, glioma, lung, cervical, gastric and prostate cancer, elucidating the mechanisms involved in modulating proliferation, apoptosis, migration, invasion, angiogenesis, and radio/chemoresistance. Furthermore, the review highlights CRNDE's potential as a multifaceted biomarker, owing to its presence in diverse biological samples and stable properties, thereby underscoring its diagnostic, therapeutic, and prognostic applications. This review aims to provide comprehensive insights of CRNDE-mediated oncogenesis and identify CRNDE as a promising target for future clinical interventions.
{"title":"CRNDE: A Pivotal Oncogenic Long Non-Coding RNA in Cancers.","authors":"Yi Zhen Hor, Shamala Salvamani, Baskaran Gunasekaran, Koh Rhun Yian","doi":"10.59249/VHYE2306","DOIUrl":"10.59249/VHYE2306","url":null,"abstract":"<p><p>Colorectal Neoplasia Differentially Expressed (CRNDE), a long non-coding RNA that was initially identified as aberrantly expressed in colorectal cancer (CRC) has also been observed to exhibit elevated expression in various other human malignancies. Recent research has accumulated substantial evidence implicating CRNDE as an oncogenic player, exerting influence over critical cellular processes linked to cancer progression. Particularly, its regulatory interactions with microRNAs and proteins have been shown to modulate pathways that contribute to carcinogenesis and tumorigenesis. This review will comprehensively outline the roles of CRNDE in colorectal, liver, glioma, lung, cervical, gastric and prostate cancer, elucidating the mechanisms involved in modulating proliferation, apoptosis, migration, invasion, angiogenesis, and radio/chemoresistance. Furthermore, the review highlights CRNDE's potential as a multifaceted biomarker, owing to its presence in diverse biological samples and stable properties, thereby underscoring its diagnostic, therapeutic, and prognostic applications. This review aims to provide comprehensive insights of CRNDE-mediated oncogenesis and identify CRNDE as a promising target for future clinical interventions.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139075606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-29eCollection Date: 2023-12-01DOI: 10.59249/BWBY8971
Shimaa A Abass, Nabil Mohie Abdel-Hamid, Ahmed M Elshazly, Walied Abdo, Sherin Zakaria
Identifying new hepatocellular carcinoma (HCC)-driven signaling molecules and discovering their molecular mechanisms are crucial for efficient and better outcomes. Recently, OMA1 and YME1L, the inner mitochondrial proteases, were displayed to be associated with tumor progression in various cancers; however, their role in HCC has not yet been studied. Therefore, we evaluated the possible role of OMA1/YME1L in HCC staging and discussed their potential role in cellular apoptosis and proliferation. Our study was performed using four groups of male albino rats: a normal control and three diethyl nitrosamine-treated groups for 8, 16, and 24 weeks. The OMA1 and YME1L, matrix-metalloproteinase-9 (MMP-9), and cyclin D1 content were measured in liver tissues, while alpha-fetoprotein (AFP) level was assessed in serum. Additionally, Ki-67 expression was evaluated by immunohistochemistry. The relative hepatic expression of Bax, and tissue inhibitor matrix metalloproteinase (TIMP-3) was measured. Herein, we confirmed for the first time that OMA1 is down-regulated while YME1L is up-regulated in HCC in the three studied stages with subsequent inhibition of apoptosis and cell cycle progression. Furthermore, these proteases have a possible role in metastasis. These newly recognized results suggested OMA1 and YME1L as possible diagnostic tools and therapeutic targets for HCC management.
{"title":"OMA1 and YME1L as a Diagnostic Panel in Hepatocellular Carcinoma.","authors":"Shimaa A Abass, Nabil Mohie Abdel-Hamid, Ahmed M Elshazly, Walied Abdo, Sherin Zakaria","doi":"10.59249/BWBY8971","DOIUrl":"10.59249/BWBY8971","url":null,"abstract":"<p><p>Identifying new hepatocellular carcinoma (HCC)-driven signaling molecules and discovering their molecular mechanisms are crucial for efficient and better outcomes. Recently, OMA1 and YME1L, the inner mitochondrial proteases, were displayed to be associated with tumor progression in various cancers; however, their role in HCC has not yet been studied. Therefore, we evaluated the possible role of OMA1/YME1L in HCC staging and discussed their potential role in cellular apoptosis and proliferation. Our study was performed using four groups of male albino rats: a normal control and three diethyl nitrosamine-treated groups for 8, 16, and 24 weeks. The OMA1 and YME1L, matrix-metalloproteinase-9 (MMP-9), and cyclin D1 content were measured in liver tissues, while alpha-fetoprotein (AFP) level was assessed in serum. Additionally, Ki-67 expression was evaluated by immunohistochemistry. The relative hepatic expression of Bax, and tissue inhibitor matrix metalloproteinase (TIMP-3) was measured. Herein, we confirmed for the first time that OMA1 is down-regulated while YME1L is up-regulated in HCC in the three studied stages with subsequent inhibition of apoptosis and cell cycle progression. Furthermore, these proteases have a possible role in metastasis. These newly recognized results suggested OMA1 and YME1L as possible diagnostic tools and therapeutic targets for HCC management.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139075612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-29eCollection Date: 2023-09-01DOI: 10.59249/RLAU6003
Mine Koprulu, Rana Muhammad Kamran Shabbir, Sara Mumtaz, Aslıhan Tolun, Sajid Malik
We present a Pakistani kinship afflicted with a syndrome with features including short stature, reduced sitting height, orofacial symptoms including prominent forehead and thick eyebrows, short and broad thorax, and variable features such as long philtrum, short broad neck, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Phenotypic variation even within different sibships was considerable. The unique combination of the phenotypic characteristics prompted us to determine the shared homozygosity regions in patient genomes and the pathogenic variants by next generation technologies like single nucleotide polymorphism (SNP) genotyping and whole exome sequencing (WES). Through these analyses, we detected homozygous OBSL1 c.848delG (p.Gly283AlafsTer54) as the causal variant. Biallelic variants in OBSL1 are known to cause Three M Syndrome 2 (3M2), a rare disorder of growth retardation with characteristic facial dysmorphism and musculoskeletal abnormalities. Affected members of the family do not have the 3M2 hallmark features of dolichocephaly, hypoplastic midface, anteverted nares, low nasal bridge, pectus excavatum, sacral hyperlordosis, spina bifida occulta, anterior wedging of thoracic vertebrae, prominent heels, and prominent talus. Moreover, they have some variable features not typical for the syndrome such as round face, disproportionate short stature, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Our study facilitated genetic diagnosis in the family, expanded the clinical phenotype for 3M2, and unraveled the considerable clinical variation within the same kinship. We conclude that unbiased molecular analyses such as WES should be more integrated into healthcare, particularly in populations with high parental consanguinity, given the potential of such analyses to facilitate diagnosis.
我们报告一名巴基斯坦亲属患有一种综合征,其特征包括身材矮小、坐高降低、口面症状包括前额突出和眉毛浓密、胸部短而宽,以及多种特征,如人中长、脖子短而宽、桶状胸、胸部后凸、性腺功能减退和尿道下裂。表型变异甚至在不同的同胞体内也是相当大的。表型特征的独特组合促使我们通过单核苷酸多态性(SNP)基因分型和全外显子组测序(WES)等下一代技术来确定患者基因组和致病性变体中的共享纯合子区域。通过这些分析,我们检测到纯合的OBSL1 c.848delG(p.Gly283AlafsTer54)是致病变体。已知OBSL1的双等位基因变异会导致Three M Syndrome 2(3M2),这是一种罕见的生长迟缓疾病,具有特征性的面部畸形和肌肉骨骼异常。受影响的家族成员没有3M2的标志性特征,如小头畸形、面中部发育不全、鼻孔前倾、低鼻梁、漏斗胸、骶骨前凸、隐性脊柱裂、胸椎前楔入、突出的跟部和突出的距骨。此外,他们有一些不典型的综合征的可变特征,如圆脸、不成比例的矮小、圆胸、胸部后凸畸形、性腺功能减退和尿道下裂。我们的研究促进了该家族的基因诊断,扩大了3M2的临床表型,并揭示了同一亲缘关系中相当大的临床变异。我们的结论是,考虑到此类分析有助于诊断的潜力,WES等无偏见的分子分析应更多地纳入医疗保健,特别是在父母血亲较高的人群中。
{"title":"Expanding OBSL1 Mutation Phenotype: Disproportionate Short Stature, Barrel Chest, Thoracic Kyphoscoliosis, Hypogonadism, and Hypospadias.","authors":"Mine Koprulu, Rana Muhammad Kamran Shabbir, Sara Mumtaz, Aslıhan Tolun, Sajid Malik","doi":"10.59249/RLAU6003","DOIUrl":"https://doi.org/10.59249/RLAU6003","url":null,"abstract":"<p><p>We present a Pakistani kinship afflicted with a syndrome with features including short stature, reduced sitting height, orofacial symptoms including prominent forehead and thick eyebrows, short and broad thorax, and variable features such as long philtrum, short broad neck, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Phenotypic variation even within different sibships was considerable. The unique combination of the phenotypic characteristics prompted us to determine the shared homozygosity regions in patient genomes and the pathogenic variants by next generation technologies like single nucleotide polymorphism (SNP) genotyping and whole exome sequencing (WES). Through these analyses, we detected homozygous <i>OBSL1</i> c.848delG (p.Gly283AlafsTer54) as the causal variant. Biallelic variants in <i>OBSL1</i> are known to cause Three M Syndrome 2 (3M2), a rare disorder of growth retardation with characteristic facial dysmorphism and musculoskeletal abnormalities. Affected members of the family do not have the 3M2 hallmark features of dolichocephaly, hypoplastic midface, anteverted nares, low nasal bridge, pectus excavatum, sacral hyperlordosis, spina bifida occulta, anterior wedging of thoracic vertebrae, prominent heels, and prominent talus. Moreover, they have some variable features not typical for the syndrome such as round face, disproportionate short stature, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Our study facilitated genetic diagnosis in the family, expanded the clinical phenotype for 3M2, and unraveled the considerable clinical variation within the same kinship. We conclude that unbiased molecular analyses such as WES should be more integrated into healthcare, particularly in populations with high parental consanguinity, given the potential of such analyses to facilitate diagnosis.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/71/d9/yjbm_96_3_367.PMC10524810.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41138066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-29eCollection Date: 2023-09-01DOI: 10.59249/SSRG6507
Syeda Farwa Naqvi, Esra Yıldız-Bölükbaşı, Muhammad Afzal, Gökhan Nalbant, Sara Mumtaz, Aslıhan Tolun, Sajid Malik
Intellectual disability (ID) involves compromised intellectual, learning and cognitive skills, and behavioral capabilities with reduced psychomotor skills. One of the preventable causes of ID is congenital hypothyroidism (CH), which may be due to biallelic mutations in thyroid peroxidase (TPO). In low- and middle-income countries with no newborn screening programs, CH poses a great risk of ID and long-term morbidity. We report two large Pakistani families with a total of 16 patients afflicted with CH. Detailed clinical and behavioral assessments, SNP-based homozygosity mapping, linkage analysis, and exome sequencing were performed. Initially, affected individuals were referred as suffering ID (in 11 of 16 patients) and developmental delay (in 14). Secondary/associated features were verbal apraxia (in 13), goiter (in 12), short stature (in 11), limb hypotonia (in 14), no pubertal onset (five of 10 of age ≥14 years), high myopia (in eight), muscle cramps (in six), and in some, variable microcephaly and enuresis/encopresis, fits, chronic fatigue, and other behavioral symptoms, which are not characteristics of CH. Molecular genetic analyses led to the discovery of homozygous variants in TPO: novel missense variant c.719A>G (p.Asp240Gly) in family 1 and rare c.2315A>G (p.Tyr772Cys) in family 2. In low-resource countries where neonatal screening programs do not include a CH test, the burden of neurodevelopmental disorders is likely to be increased due to untreated CH. Secondly, in the background of the high prevalence of recessive disorders due to high parental consanguinity, the severe manifestation of TPO-deficiency mimics a wide range of neurological and other presentations posing a diagnostic dilemma.
{"title":"Homozygous Mutations in Thyroid Peroxidase (TPO) in Hypothyroidism with Intellectual Disability, Developmental Delay, and Hearing and Ocular Anomalies in Two Families: Severe Manifestation of Untreated TPO-deficiency Poses a Diagnostic Dilemma.","authors":"Syeda Farwa Naqvi, Esra Yıldız-Bölükbaşı, Muhammad Afzal, Gökhan Nalbant, Sara Mumtaz, Aslıhan Tolun, Sajid Malik","doi":"10.59249/SSRG6507","DOIUrl":"10.59249/SSRG6507","url":null,"abstract":"<p><p>Intellectual disability (ID) involves compromised intellectual, learning and cognitive skills, and behavioral capabilities with reduced psychomotor skills. One of the preventable causes of ID is congenital hypothyroidism (CH), which may be due to biallelic mutations in <i>thyroid peroxidase</i> (<i>TPO</i>). In low- and middle-income countries with no newborn screening programs, CH poses a great risk of ID and long-term morbidity. We report two large Pakistani families with a total of 16 patients afflicted with CH. Detailed clinical and behavioral assessments, SNP-based homozygosity mapping, linkage analysis, and exome sequencing were performed. Initially, affected individuals were referred as suffering ID (in 11 of 16 patients) and developmental delay (in 14). Secondary/associated features were verbal apraxia (in 13), goiter (in 12), short stature (in 11), limb hypotonia (in 14), no pubertal onset (five of 10 of age ≥14 years), high myopia (in eight), muscle cramps (in six), and in some, variable microcephaly and enuresis/encopresis, fits, chronic fatigue, and other behavioral symptoms, which are not characteristics of CH. Molecular genetic analyses led to the discovery of homozygous variants in <i>TPO</i>: novel missense variant c.719A>G (p.Asp240Gly) in family 1 and rare c.2315A>G (p.Tyr772Cys) in family 2. In low-resource countries where neonatal screening programs do not include a CH test, the burden of neurodevelopmental disorders is likely to be increased due to untreated CH. Secondly, in the background of the high prevalence of recessive disorders due to high parental consanguinity, the severe manifestation of <i>TPO</i>-deficiency mimics a wide range of neurological and other presentations posing a diagnostic dilemma.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ac/03/yjbm_96_3_347.PMC10524819.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41162193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-29eCollection Date: 2023-09-01DOI: 10.59249/LNDZ2964
Mohammad A Zafar, Bulat A Ziganshin, Yupeng Li, Nicolai P Ostberg, John A Rizzo, Maryann Tranquilli, Sandip K Mukherjee, John A Elefteriades
This issue of the Yale Journal of Biology and Medicine (YJBM) focuses on Big Data and precision analytics in medical research. At the Aortic Institute at Yale New Haven Hospital, the vast majority of our investigations have emanated from our large, prospective clinical database of patients with thoracic aortic aneurysm (TAA), supplemented by ultra-large genetic sequencing files. Among the fundamental clinical and scientific discoveries enabled by application of advanced statistical and artificial intelligence techniques on these clinical and genetic databases are the following: From analysis of Traditional "Big Data" (Large data sets). 1. Ascending aortic aneurysms should be resected at 5 cm to prevent dissection and rupture. 2. Indexing aortic size to height improves aortic risk prognostication. 3. Aortic root dilatation is more malignant than mid-ascending aortic dilatation. 4. Ascending aortic aneurysm patients with bicuspid aortic valves do not carry the poorer prognosis previously postulated. 5. The descending and thoracoabdominal aorta are capable of rupture without dissection. 6. Female patients with TAA do more poorly than male patients. 7. Ascending aortic length is even better than aortic diameter at predicting dissection. 8. A "silver lining" of TAA disease is the profound, lifelong protection from atherosclerosis. From Modern "Big Data" Machine Learning/Artificial Intelligence analysis: 1. Machine learning models for TAA: outperforming traditional anatomic criteria. 2. Genetic testing for TAA and dissection and discovery of novel causative genes. 3. Phenotypic genetic characterization by Artificial Intelligence. 4. Panel of RNAs "detects" TAA. Such findings, based on (a) long-standing application of advanced conventional statistical analysis to large clinical data sets, and (b) recent application of advanced machine learning/artificial intelligence to large genetic data sets at the Yale Aortic Institute have advanced the diagnosis and medical and surgical treatment of TAA.
{"title":"\"Big Data\" Analyses Underlie Clinical Discoveries at the Aortic Institute.","authors":"Mohammad A Zafar, Bulat A Ziganshin, Yupeng Li, Nicolai P Ostberg, John A Rizzo, Maryann Tranquilli, Sandip K Mukherjee, John A Elefteriades","doi":"10.59249/LNDZ2964","DOIUrl":"10.59249/LNDZ2964","url":null,"abstract":"<p><p>This issue of the <i>Yale Journal of Biology and Medicine</i> (<i>YJBM</i>) focuses on Big Data and precision analytics in medical research. At the Aortic Institute at Yale New Haven Hospital, the vast majority of our investigations have emanated from our large, prospective clinical database of patients with thoracic aortic aneurysm (TAA), supplemented by ultra-large genetic sequencing files. Among the fundamental clinical and scientific discoveries enabled by application of advanced statistical and artificial intelligence techniques on these clinical and genetic databases are the following: <b>From analysis of Traditional \"Big Data\" (Large data sets)</b>. 1. Ascending aortic aneurysms should be resected at 5 cm to prevent dissection and rupture. 2. Indexing aortic size to height improves aortic risk prognostication. 3. Aortic root dilatation is more malignant than mid-ascending aortic dilatation. 4. Ascending aortic aneurysm patients with bicuspid aortic valves do not carry the poorer prognosis previously postulated. 5. The descending and thoracoabdominal aorta are capable of rupture without dissection. 6. Female patients with TAA do more poorly than male patients. 7. Ascending aortic length is even better than aortic diameter at predicting dissection. 8. A \"silver lining\" of TAA disease is the profound, lifelong protection from atherosclerosis. <b>From Modern \"Big Data\" Machine Learning/Artificial Intelligence analysis</b>: 1. Machine learning models for TAA: outperforming traditional anatomic criteria. 2. Genetic testing for TAA and dissection and discovery of novel causative genes. 3. Phenotypic genetic characterization by Artificial Intelligence. 4. Panel of RNAs \"detects\" TAA. Such findings, based on (a) long-standing application of advanced conventional statistical analysis to large clinical data sets, and (b) recent application of advanced machine learning/artificial intelligence to large genetic data sets at the Yale Aortic Institute have advanced the diagnosis and medical and surgical treatment of TAA.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f5/65/yjbm_96_3_427.PMC10524815.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41173041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-29eCollection Date: 2023-09-01DOI: 10.59249/UDRG5942
Natasia S Courchesne-Krak, Carla B Marienfeld, Wayne Kepner
Background: Substance-related diagnoses (SRDs) are a common healthcare presentation. This study identified sociodemographic and health-related characteristics associated with having an SRD as the primary reason for a clinical encounter compared to those with an SRD who are treated for other reasons. Methods: Electronic health record (EHR) data on patients with an SRD (n=12,358, ages 18-90) were used to assess if an SRD was the primary reason for a clinical encounter from January 1, 2012-January 1, 2018. Patients were matched on key demographic characteristics at a 1:1 ratio. Adjusting for covariates, odds ratios, and 95% confidence intervals were calculated. Results: In the matched cohort of 8,630, most reported male sex (65.8%), White race (70.0%), and single marital status (62.7%) with a mean age of 47.2 (SD=14.6). Patient reported female sex, Black race, age 70+, married status, and low-income (<$50,000) were associated with a lower likelihood of presenting to care for an SRD as the primary reason for a clinical encounter. A nicotine-, alcohol-, opioid-, or stimulant-related diagnosis was associated with a higher likelihood of presenting to care for an SRD as the primary reason for the clinical visit. Conclusion: This is the first study to investigate whether sociodemographic and health-related characteristics were associated with having an SRD as the primary reason for a clinical encounter. Using rigorous methods, we investigated a unique clinical question adding new knowledge to predictors of patients seeking clinical care. Understanding these predictors can help us better align service provision with population needs and inform new approaches to tailoring care.
{"title":"What Brings You in Today? Sex, Race, Substance Type, and Other Sociodemographic and Health-Related Characteristics Predict if Substance Use is the Main Reason for a Clinical Encounter.","authors":"Natasia S Courchesne-Krak, Carla B Marienfeld, Wayne Kepner","doi":"10.59249/UDRG5942","DOIUrl":"10.59249/UDRG5942","url":null,"abstract":"<p><p><b>Background</b>: Substance-related diagnoses (SRDs) are a common healthcare presentation. This study identified sociodemographic and health-related characteristics associated with having an SRD as the primary reason for a clinical encounter compared to those with an SRD who are treated for other reasons. <b>Methods</b>: Electronic health record (EHR) data on patients with an SRD (n=12,358, ages 18-90) were used to assess if an SRD was the primary reason for a clinical encounter from January 1, 2012-January 1, 2018. Patients were matched on key demographic characteristics at a 1:1 ratio. Adjusting for covariates, odds ratios, and 95% confidence intervals were calculated. <b>Results</b>: In the matched cohort of 8,630, most reported male sex (65.8%), White race (70.0%), and single marital status (62.7%) with a mean age of 47.2 (SD=14.6). Patient reported female sex, Black race, age 70+, married status, and low-income (<$50,000) were associated with a lower likelihood of presenting to care for an SRD as the primary reason for a clinical encounter. A nicotine-, alcohol-, opioid-, or stimulant-related diagnosis was associated with a higher likelihood of presenting to care for an SRD as the primary reason for the clinical visit. <b>Conclusion</b>: This is the first study to investigate whether sociodemographic and health-related characteristics were associated with having an SRD as the primary reason for a clinical encounter. Using rigorous methods, we investigated a unique clinical question adding new knowledge to predictors of patients seeking clinical care. Understanding these predictors can help us better align service provision with population needs and inform new approaches to tailoring care.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/10/e2/yjbm_96_3_277.PMC10524817.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41136392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-29eCollection Date: 2023-09-01DOI: 10.59249/UTCP9818
Hamna Shahid, Nazish Shakoor, Anisa Bibi, Asma Saleem Qazi, Rida Fatima Saeed, Aqeela Nawaz, Sajid Malik, Sara Mumtaz
Spondylocarpotarsal synostosis (SCT) syndrome is a very rare and severe form of skeletal dysplasia. The hallmark features of SCT are disproportionate short stature, scoliosis, fusion of carpal and tarsal bones, and clubfoot. Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Homozygous variants in FLNB are known to cause SCT. This study was aimed to investigate the phenotypic and genetic basis of unique presentation of SCT syndrome segregating in a consanguineous Pakistani family. Three of the four affected siblings evaluated had severe short stature, short trunk, short neck, kyphoscoliosis, pectus carinatum, and winged scapula. The subjects had difficulty in walking and gait problems and complained of knee pain and backache. Roentgenographic examination of the eldest patient revealed gross anomalies in the axial skeleton including thoracolumbar and cervical fusion of ribs, severe kyphoscoliosis, thoracic and lumbar lordosis, coxa valga, fusion of certain carpals and tarsals, and clinodactyly. The patients had normal faces and lacked other typical features of SCT like cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Whole exome sequencing (WES) of two affected siblings led to the discovery of a rare stop-gain variant c.220C>T (p.(Gln74*)) in exon 1 of the FLNB gene. The variant was homozygous and segregated with the malformation in this family. This study reports extensive phenotypic variability in SCT and expands the mutation spectrum of FLNB.
{"title":"A Stop-gain Variant c.220C>T (p.(Gln74*)) in <i>FLNB</i> Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family.","authors":"Hamna Shahid, Nazish Shakoor, Anisa Bibi, Asma Saleem Qazi, Rida Fatima Saeed, Aqeela Nawaz, Sajid Malik, Sara Mumtaz","doi":"10.59249/UTCP9818","DOIUrl":"https://doi.org/10.59249/UTCP9818","url":null,"abstract":"<p><p>Spondylocarpotarsal synostosis (SCT) syndrome is a very rare and severe form of skeletal dysplasia. The hallmark features of SCT are disproportionate short stature, scoliosis, fusion of carpal and tarsal bones, and clubfoot. Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Homozygous variants in <i>FLNB</i> are known to cause SCT. This study was aimed to investigate the phenotypic and genetic basis of unique presentation of SCT syndrome segregating in a consanguineous Pakistani family. Three of the four affected siblings evaluated had severe short stature, short trunk, short neck, kyphoscoliosis, pectus carinatum, and winged scapula. The subjects had difficulty in walking and gait problems and complained of knee pain and backache. Roentgenographic examination of the eldest patient revealed gross anomalies in the axial skeleton including thoracolumbar and cervical fusion of ribs, severe kyphoscoliosis, thoracic and lumbar lordosis, coxa valga, fusion of certain carpals and tarsals, and clinodactyly. The patients had normal faces and lacked other typical features of SCT like cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Whole exome sequencing (WES) of two affected siblings led to the discovery of a rare stop-gain variant c.220C>T (p.(Gln74*)) in exon 1 of the <i>FLNB</i> gene. The variant was homozygous and segregated with the malformation in this family. This study reports extensive phenotypic variability in SCT and expands the mutation spectrum of <i>FLNB</i>.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/87/cc/yjbm_96_3_383.PMC10524816.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41140085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-29eCollection Date: 2023-09-01DOI: 10.59249/VUPM2510
Austen N Knapp, Theodore Leng, Ehsan Rahimy
Ophthalmology stands at the vanguard of incorporating big data into medicine, as exemplified by the integration of The Intelligent Research in Sight (IRIS) Registry. This synergy cultivates patient-centered care, demonstrates real world efficacy and safety data for new therapies, and facilitates comprehensive population health insights. By evaluating the creation and utilization of the world's largest specialty clinical data registry, we underscore the transformative capacity of data-driven medical paradigms, current shortcomings, and future directions. We aim to provide a scaffold for other specialties to adopt big data integration into medicine.
{"title":"Ophthalmology at the Forefront of Big Data Integration in Medicine: Insights from the IRIS Registry Database.","authors":"Austen N Knapp, Theodore Leng, Ehsan Rahimy","doi":"10.59249/VUPM2510","DOIUrl":"https://doi.org/10.59249/VUPM2510","url":null,"abstract":"<p><p>Ophthalmology stands at the vanguard of incorporating big data into medicine, as exemplified by the integration of The Intelligent Research in Sight (IRIS) Registry. This synergy cultivates patient-centered care, demonstrates real world efficacy and safety data for new therapies, and facilitates comprehensive population health insights. By evaluating the creation and utilization of the world's largest specialty clinical data registry, we underscore the transformative capacity of data-driven medical paradigms, current shortcomings, and future directions. We aim to provide a scaffold for other specialties to adopt big data integration into medicine.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/32/1f/yjbm_96_3_421.PMC10524808.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41159182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}