Genetic analysis of a child with D bifunctional protein deficiency born to a consanguineous pedigree / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a child with D bifunctional protein deficiency (DBPD) born to a consanguineous pedigree.@*METHODS@#A child with DBPD who was admitted to the First Affiliated Hospital of Hainan Medical College on January 6, 2022 due to hypotonia and global developmental delay was selected as the study subject. Clinical data of her pedigree members were collected. Peripheral blood samples of the child, her parents and elder sisters were collected and subjected to whole exome sequencing. Candidate variant was validated by Sanger sequencing and bioinformatic analysis.@*RESULTS@#The child, a 2-year-and-9-month-old female, had featured hypotonia, growth retardation, unstable head lift, and sensorineural deafness. Serum long-chain fatty acids were elevated, and auditory brainstem evoked potentials had failed to elicit V waves in both ears with 90 dBnHL stimulation. Brain MRI revealed thinning of corpus callosum and white matter hypoplasia. The child's parents were secondary cousins. Their elder daughter had a normal phenotype and no clinical symptoms related to DBPD. Elder son had frequent convulsions, hypotonia and feeding difficulties after birth, and had died one and a half month later. Genetic testing revealed that the child had harbored homozygous c.483G>T (p.Gln161His) variants of the HSD17B4 gene, for which both of her parents and elder sisters were carriers. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.483G>T (p.Gln161His) was rated as a pathogenic variant (PM1+PM2_Supporting+PP1+PP3+PP4).@*CONCLUSION@#The homozygous c.483G>T (p.Gln161His) variants of the HSD17B4 gene caused by the consanguineous marriage probably underlay the DBPD in this child.

Overcoming chemotherapy resistance simultaneous drug-efflux circumvention and mitochondrial targeting

Multidrug resistance (MDR) has been considered as a huge challenge to the effective chemotherapy. Therefore, it is necessary to develop new strategies to effectively overcome MDR. Here, based on the previous research of -(2-hydroxypropyl)methacrylamide (HPMA) polymer-drug conjugates, we designed an effective system that combined drug-efflux circumvention and mitochondria targeting of anticancer drug doxorubicin (Dox). Briefly, Dox was modified with mitochondrial membrane penetrating peptide (MPP) and then attached to (HPMA) copolymers (P-M-Dox). Our study showed that macromolecular HPMA copolymers successfully bypassed drug efflux pumps and escorted Dox into resistant MCF-7/ADR cells endocytic pathway. Subsequently, the mitochondria accumulation of drugs was significantly enhanced with 11.6-fold increase by MPP modification. The excellent mitochondria targeting then resulted in significant enhancement of reactive oxygen species (ROS) as well as reduction of adenosine triphosphate (ATP) production, which could further inhibit drug efflux and resistant cancer cell growth. By reversing Dox resistance, P-M-Dox achieved much better suppression in the growth of 3D MCF-7/ADR tumor spheroids compared with free Dox. Hence, our study provides a promising approach to treat drug-resistant cancer through simultaneous drug efflux circumvention and direct mitochondria delivery.

Research on the clinical value of urinary NTx,serum BAP and BMD in patients with bone metastasis from malignant tumors / 重庆医学

Objective To evaluate the variance and clinical significance of urinary pyridinoline cross-linked N-telopeptides of Type Ⅰ collagen(uNTx) ,serum bone specific alkaline phosphates(sBAP) and Bone mineral density(BMD) in patients with bone metastasis malignant tumors .Methods The levels of 53 case patients′,who with bone metastasis ,uNTx and sBAP were measured by ELISA and BMD was detected by dual energy x-ray absorptiometer .40 cases of non-bone metastasis people was assayed .Results The levels of all bone markers in patients with bone metastasis was significantly higher than in the patients without bone metas-tasis(P0 .05) . BMD decreased in patients with bone metastasis group ,but it was no difference in the non-bone metastasis(P>0 .05) .Conclusion uNTx and sBAP are helpful for early diagnosis and prevention of patients with bone metastasis from malignant tumors .Patients with malignant gumor is often accompanied by a decrease in BMD .