Epidermal growth factor receptor inhibition potentiates chemotherapeutics-mediated sensitization of metastatic breast cancer stem cells.

BACKGROUND: Metastasis has been a cause of the poor prognosis and cancer relapse of triple-negative breast cancer (TNBC) patients. The metastatic nature of TNBC is contributed by the breast cancer stem cells (CSCs) which have been implicated in tumorigenesis. Higher expression of epidermal growth factor receptor (EGFR) in breast CSCs has been used as a molecular target for breast cancer therapeutics. Thus, it necessitates the design and generation of efficacious EGFR inhibitors to target the downstream signaling associated with the cellular proliferation and tumorigenesis of breast cancer. AIM: To generate efficacious EGFR inhibitors that can potentiate the chemotherapeutic-mediated mitigation of breast cancer tumorigenesis. METHODS AND RESULTS: We identified small molecule EGFR inhibitors using molecular docking studies. In-vitro screening of the compounds was undertaken to identify the cytotoxicity profile of the small-molecule EGFR inhibitors followed by evaluation of the non-cytotoxic compounds in modulating the doxorubicin-induced migration, in-vitro tumorigenesis potential, and their effect on the pro-apoptotic genes' and protein markers' expression in TNBC cells. Compound 1e potentiated the doxorubicin-mediated inhibitory effect on proliferation, migration, in-vitro tumorigenesis capacity, and induction of apoptosis in MDA-MB-231 cells, and in the sorted CD24+-breast cancer cells and CD24-/CD44+-breast CSC populations. Orthotopic xenotransplantation of the breast CSCs-induced tumors in C57BL/6J mice was significantly inhibited by the low dose of Doxorubicin in the presence of compound 1e as depicted by molecular and immunohistochemical analysis. CONCLUSION: Thus, the study suggests that EGFR inhibition-mediated sensitization of the aggressive and metastatic breast CSCs in TNBCs toward chemotherapeutics may reduce the relapse of the disease.

HLA allele frequency of HLA-A, -B, -C, -DRB1 and -DQB1 in Indian recurrent implantation failure and recurrent pregnancy loss couples - A retrospective study.

The maternal-fetal interaction has been hypothesized to involve the human leucocyte antigen (HLA). It has been suggested that excessive HLA antigen sharing between spouses is a mechanism causing maternal hyporesponsiveness to paternal antigens encountered during pregnancy and thus leading to a miscarriage. Participants in this retrospective study are RIF and RPL couples who visited Gunasheela Surgical and Maternity Hospital, Bangalore, India from November 2019 to September 2022. A total of 40 couples with RIF and 195 couples with RPL are included in the study. We observed that the DQB1*02:01:01 allele is associated with an increase in risk of both RIF and RPL, while the C*12:02:01 allele increases risk of only RPL. On the contrary, DQB1*02:02:01 and DQB1*06:03 alleles appear to be protective against both RPL and RIF. In addition, the C*07:02:01 allele was observed to be protective against RPL. In conclusion, C*12:02:01 and DQB1*02:01:01 could play a major role in RPL which is consistent with other studies, while DQB1*02:01:01 is the risk allele in our RIF group. The protective alleles C*07:02:01 in the RPL group, DQB1*02:02:01, and DQB1*06:03 in both RIF and RPL, were discovered for the first time. Allele frequencies will vary in population-based studies depending on the ethnicities of the cohort. Meta-analysis and antibody testing will provide additional insights on whether and how this data can be adopted into clinical practices.

Future transition in climate extremes over Western Ghats of India based on CMIP6 models.

The effect of climate change on the tropical river catchments in the Western Ghats of India is studied using the Coupled Model Intercomparison Project-6 data (CMIP-6). Multi-model ensembles of rainfall and temperature are constructed using the Random Forest ensemble technique for bias-corrected GCMs in the near future (2014-2050) and far future (2051-2100) horizons. For the two catchments each in the southern, central, and northern Ghats, the trend in minimum and maximum temperatures, precipitation, and other indices are calculated. By 2100, dry sub-humid and humid catchments will see a higher increase in mean annual temperature than per-humid central catchments. In future decades, the warm days and nights increase by 45-50% and 40-70%, respectively, with twofold warming in the winter season. Under a climate change scenario, annual rainfall increases in Vamanapuram, Ulhas, and Purna, while Chaliyar, Netravati, and Aghanashini catchments experience a decrease in rainfall in the far future with an increase in pre-monsoon rainfall. The southern catchments are anticipated to have contrasting variations in the rainfall extremes; northern catchments face a substantial increase in very wet to extremely wet days and medium to heavy rainfall. In all catchments (excluding Vamanapuram), cumulative wet days increase with a decrease in cumulative dry days. After the mid-twenty-first century, humid to per-humid catchments encompass an increase in cool nights, whereas it disappears in dry sub-humid catchments of the Ghat. Interestingly, warming tendencies begin to slow down after 2050. This investigation can assist in comprehending the regional climate extremes in the Western Ghats to formulate better climate risk planning and adaptation strategies.

Preimplantation Genetic Testing for Couples with Balanced Chromosomal Rearrangements.

Background: Chromosomal rearrangements play an important role in infertility. Carriers of chromosomal rearrangements have a lower chance of producing normal or balanced gametes due to abnormal segregation of chromosomes at meiosis, which leads to recurrent spontaneous abortions and infertility. Preimplantation genetic testing for structural chromosome rearrangements (PGT-SR) is offered to couples who have balanced chromosomal rearrangements in order to select embryos with a balanced karyotype prior to implantation, thereby increasing the chances of pregnancy. The purpose of the current study was to assess the outcomes of PGT-SR in patients carrying various balanced chromosomal rearrangements and to assess their clinical pregnancy outcome after in vitro fertilization (IVF). Methods: In this study, infertile couples with balanced chromosomal abnormalities undergoing PGT-SR were retrospectively analyzed at a single fertility center from January 2016 to December 2019. Results: PGT-SR was performed on 87 embryos from 22 couples in whom one partner carried a balanced translocation or an inversion. Fifty-seven (65.5%) of these embryos had unbalanced or sporadic aneuploidies, 30 (34.5%) embryos were normal or chromosomally balanced, which were then transferred in 18 couples. A higher rate of unbalanced translocations in comparison to sporadic aneuploidies was observed in couples with reciprocal translocation. The live birth rate per embryo transfer was found to be 66.6% (12/18). Conclusion: PGT-SR is a useful tool in selecting normal or balanced embryos for transfer in IVF, which could lead to a pregnancy by reducing the chance of miscarriages due to chromosome aneuploidy in couples with balanced chromosomal rearrangements.

Molecular and clinical profiling in a large cohort of Asian Indians with glycogen storage disorders.

Glycogen storage disorders occur due to enzyme deficiencies in the glycogenolysis and gluconeogenesis pathway, encoded by 26 genes. GSD's present with overlapping phenotypes with variable severity. In this series, 57 individuals were molecularly confirmed for 7 GSD subtypes and their demographic data, clinical profiles and genotype-phenotype co-relations are studied. Genomic DNA from venous blood samples was isolated from clinically affected individuals. Targeted gene panel sequencing covering 23 genes and Sanger sequencing were employed. Various bioinformatic tools were used to predict pathogenicity for new variations. Close parental consanguinity was seen in 76%. Forty-nine pathogenic variations were detected of which 27 were novel. Variations were spread across GSDIa, Ib, III, VI, IXa, b and c. The largest subgroup was GSDIII in 28 individuals with 24 variations (12 novel) in AGL. The 1620+1G>C intronic variation was observed in 5 with GSDVI (PYGL). A total of eleven GSDIX are described with the first Indian report of type IXb. This is the largest study of GSDs from India. High levels of consanguinity in the local population and employment of targeted sequencing panels accounted for the range of GSDs reported here.

Evaluation of Soft Tissue and Airway Changes in Individuals Treated with Mini-Implant Assisted Rapid Palatal Expansion (MARPE).

INTRODUCTION: Mini-implant assisted rapid palatal expansion (MARPE) is gradually becoming the treatment of choice to correct the transverse dimension, exceeding the limitations of conventional RME devices. One of the key factors for orthodontic diagnosis and treatment planning apart from a stable occlusion is a balanced and aesthetic facial profile that is influenced by maxillary expansion. Similarly, it also affects the anatomy and physiology of the nasal cavity since nasal airflow is a continuous stimulus for lowering of the palate and for lateral maxillary growth. Hence, there is a need to conduct further research on the effects of MARPE on the facial soft tissues as well as the airway, enabling the orthodontist to reach a more accurate diagnosis as well as aid in the treatment planning process. AIMS AND OBJECTIVES: This retrospective three-dimensional study was planned and designed with the objective of measuring facial soft tissue and airway changes in individuals treated with mini-implant assisted rapid palatal expansion (MARPE) using CBCT. MATERIALS AND METHODS: This study was carried out on CBCT records of 10 patients in the age group of 18-30 years. These records were then imported into Romexis software and calibrated. The facial soft tissue and airway parameters were measured for each individual at selected landmarks and compared before and after expansion. RESULT: Statistically significant differences in the soft tissue parameters were observed, which included an increased H-angle, increased soft tissue subnasal to H-line and a decreased soft palate surface area after MARPE.

Preimplantation genetic testing for aneuploidy (PGT-A)-a single-center experience.

PURPOSE: The aim of this study was to determine the prevalence and nature of human embryonic aneuploidy based on the preimplantation genetic testing for aneuploidy (PGT-A), the distribution of aneuploidy across the individual chromosomes, and their relationship to maternal age. METHODS: This is a retrospective cohort study conducted at a single center. The study includes subjects who opted for PGT-A in their in vitro fertilization (IVF) cycle from 2016 to 2020. PGT-A was performed on 1501 embryos from 488 patients in 535 cycles. PGT-A was performed using NGS-based technique on Ion Torrent PGM (Life Technologies). Analysis was performed to determine the (i) frequency of the aneuploidy, (ii) the chromosome most commonly affected, (iii) relationship between maternal age and the rate of aneuploidy, and (iv) incidence of segmental aneuploidy. RESULTS: The overall frequency of aneuploidy was observed to be 46.8%. The incidence of aneuploidy rate was ~ 28% at maternal age < 30 years which steadily increased to ~ 67% in women above 40 years. High frequency of aneuploidy was observed in chromosomes 16, 22, 21, and 15. Segmental abnormalities, involving loss or gain of chromosomal fragments, were observed at a frequency of 5.3%, and highest incidence of segmental gain was observed on the q-arm of chromosome 9. CONCLUSION: The study provides important information regarding the frequency of the aneuploidy in IVF cohort and the most frequent chromosomal abnormality. The study further emphasizes the relationship between maternal age and aneuploidy. This study has important implications which help clinicians and genetic counselors in providing information in patient counseling.

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics.

Epidermal Growth Factor Receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity, is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that triggers tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells, thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Furthermore, the mechanisms of action of potential molecules at various stages of drug development, as well as clinically approved drugs for breast cancer treatment, are illustrated.

Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations.

BACKGROUND: Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation. METHODS: Individuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced. RESULTS: Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%). CONCLUSION: The clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.

Localization of the SRY Gene on Chromosome 3 in a Patient with Azoospermia and a Complex Karyotype 45,X/46,X,i(Y)(q10)/46,XX/ 47,XX,i(Y)(q10).

This study aimed to identify the cause of azoospermia in a 38-year-old infertile man who was referred for genetic testing. Cytogenetic evaluation was performed by G-banding, C-banding, and FISH using centromeric probes for chromosomes X and Y and showed the presence of a monocentric isochromosome Y with a complex, mosaic karyotype 45,X/46,X,i(Y)(q10)/46,XX/47,XX,i(Y)(q10). Multiplex PCR for the commonly deleted genes in the AZFa, AZFb, and AZFc regions of the Y chromosome was performed and indicated the presence of all 3 regions. Further, PCR amplification followed by DNA sequencing of the SRY gene was done, which ruled out mutations in that gene. To identify the position of the SRY gene, FISH using a locus-specific probe was used and showed that the gene had been translocated to chromosome 3. Subtelomere FISH for 3q and Yp evidenced that the subtelomeric region of the Y chromosome was found on the terminal region of 3q. The clinical symptoms of the patient can be attributed to this abnormal genotype. The importance of genetic testing in infertile patients and the need for genetic counselling to prevent the transmission of the defect are emphasized.

A rare presentation of lobular panniculitis in the oral cavity of a 2-year-old patient.

Pannicultis is a rare disorder which usually affects the organ and tissue which are abundant in fat cells. It causes fatty degeneration of the fat cells and the diagnosis is usually made histologically. Here we present you a rare case of lobular pannicultis which occurred in a 2 year old patient in its oral cavity.