Identifying Mechanisms of Resistance by Circulating Tumor DNA in EVOLVE, a Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer at Time of PARP Inhibitor Progression.

PURPOSE: To evaluate the use of blood cell-free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high-grade serous ovarian cancer (HGSOC). EXPERIMENTAL DESIGN: We used targeted sequencing (TS) to analyze 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled in a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib (PARPi) after progression on PARPi alone. cfDNA was collected at baseline, before treatment cycle 2, and at end of treatment. These were compared with whole-exome sequencing (WES) of baseline tumor tissues. RESULTS: At baseline (time of initial PARPi progression), cfDNA tumor fractions were 0.2% to 67% (median, 3.25%), and patients with high ctDNA levels (>15%) had a higher tumor burden (sum of target lesions; P = 0.043). Across all timepoints, cfDNA detected 74.4% of mutations known from prior tumor WES, including three of five expected BRCA1/2 reversion mutations. In addition, cfDNA identified 10 novel mutations not detected by WES, including seven TP53 mutations annotated as pathogenic by ClinVar. cfDNA fragmentation analysis attributed five of these novel TP53 mutations to clonal hematopoiesis of indeterminate potential (CHIP). At baseline, samples with significant differences in mutant fragment size distribution had shorter time to progression (P = 0.001). CONCLUSIONS: Longitudinal testing of cfDNA by TS provides a noninvasive tool for detection of tumor-derived mutations and mechanisms of PARPi resistance that may aid in directing patients to appropriate therapeutic strategies. With cfDNA fragmentation analyses, CHIP was identified in several patients and warrants further investigation.

Apple Peel Deformity and Malrotation of Gut: Autopsy Findings of a Rare Cause of Mortality in Utero.

One-third of all intestinal obstructions in the newborn are caused by atresias. The most common site is the duodenum followed by jejunoileal and colonic locations. Herein we report the autopsy findings of a rare case of jejunoileal atresia associated with malrotation of gut. Autopsy performed on a 36 weeks old male fetus still birth, born of a non-consanguineous marriage, demonstrated jejunoileal atresia with apple peel deformity and malrotation of gut. Although the diagnosis was established in the prenatal period, in utero fetal demise occurred before definitive surgical intervention could be done. This case highlights the importance of early diagnosis and intervention.

The Spectrum of Chromosomal Abnormalities and Endocrine Profile of Male Infertility with Nonobstructive Semen Abnormality: A Case-Control Study.

BACKGROUND: Primary infertility is a common occurrence which affects approximately 15% of couples who desire to begin their family. Chromosomal abnormalities are well-established causes of pregnancy loss but may also have a role in explaining the cause of male infertility, especially with nonobstructive semen abnormalities. Hence, awareness regarding safety of artificial reproductive technology in these individuals due to underlying sperm aneuploidy is required. AIMS: The aims of the study are to determine the prevalence of chromosomal abnormalities in primary infertile males with nonobstructive semen abnormalities and correlate with their endocrine profile. STUDY DESIGN: A case-control study, in which 100 males with primary infertility and non-obstructive semen abnormalities were evaluated for chromosomal abnormality and hormonal profile; and were compared with 50 healthy males with normal semen analysis and at least one biological child. MATERIALS AND METHODS: Blood T-lymphocytes were cultured using RPMI-1640 medium for obtaining metaphases and chromosomal analysis. STATISTICAL ANALYSIS: SPSS software and Student's t-test were used. A p < 0.05 was considered statistically significant. RESULTS: Azoospermia (81%) was the most common nonobstructive semen abnormality. Overall prevalence of major chromosomal abnormalities and polymorphic variants was 16% and 7%, respectively. Klinefelter syndrome was the most common sex chromosomal numerical abnormality seen in 6.17% of cases with azoospermia. All healthy control males had 46, XY karyotype. Higher levels of follicle-stimulating hormone and luteinizing hormone and lower levels of testosterone along with testicular volumes were observed in infertile males with abnormal karyotype (p < 0.05). CONCLUSION: Primary infertile males with nonobstructive semen abnormality have high frequency of chromosomal aberrations, which justify the requirement of cytogenetic testing in these patients.

Premature Ovarian Failure Related to Trisomy X: Two Case Reports with an Aberrant 47, XXX Karyotype.

Trisomy X syndrome is a sex chromosome aneuploidy with a variable clinical presentation at different stages of life. We present two asyndromic females with primary infertility and features of premature ovarian failure (POF). The first case was a nonmosaic trisomy X with poor ovarian reserve on pelvic ultrasound and elevated gonadotropins, while the second case was a mosaic trisomy X who had partly preserved ovarian reserve with normal gonadotropins. The 47,XXX syndrome is a relatively uncommon presentation of POF, leading to infertility and can be missed clinically because of its variable presentation. Therefore, we suggest that genetic testing should be a part of early workup in young women presenting with primary infertility and POF for detecting chromosomal aneuploidies, which will require genetic counseling and alter the management.

Insight into the properties of MnO2-Co3O4-CeO2 catalyst series for the selective catalytic reduction of NOx by C3H6 and NH3.

A series of MnO2-Co3O4-CeO2 catalysts with different ceria loading (0.75, 1.26 and 1.88 Ce/Mn molar ratio) were synthesized by a co-precipitation technique and the catalytic activity was tested for selective catalytic reduction of NOx by C3H6 or NH3. The catalysts were characterized by various physicochemical techniques to examine the effect of ceria loading on the properties of catalysts, such as crystallinity of metal species, surface area, porosity, and acidity using physical adsorption analysis, SEM-EDX, H2-TPR, XRD, NH3-TPD and in-situ FTIR spectroscopy. Ceria loading had a significant effect on the reduction of NOx, with the catalyst having low amount of ceria loading (Ce/Mn = 0.75) showing excellent performance at low-temperature conditions, but the activity declined at higher temperature. The high ceria loading (Ce/Mn = 1.88) catalyst showed poor activity compared to the counterparts owing to the lower number of acid sites and the resulting lower adsorption capacity.

Glycerol Waste Valorization to Mesoxalic Acid Over a Bimetallic Pt-Pd/CNT Catalyst in Alkaline Medium.

Glycerol electro-oxidation offers a green route to produce the high value added chemicals. Here in, we report the glycerol electro-oxidation over a series of multi walled carbon nano tubes supported monometallic (Pt/CNT and Pd/CNT) and bimetallic (Pt-Pd/CNT) catalysts in alkaline medium. The cyclic voltammetry, linear sweep voltammetry and chronoamperometry measurements were used to evaluate the activity and stability of the catalysts. The Pt-Pd/CNT electrocatalyst exhibited the highest activity in terms of higher current density (129.25 A/m²) and electrochemical surface area (382 m²/g). The glycerol electro-oxidation products formed at a potential of 0.013 V were analyzed systematically by high performance liquid chromatography. Overall, six compounds were found including mesoxalic acid, 1,3-dihydroxyacetone, glyceraldehyde, glyceric acid, tartronic acid and oxalic acid. A highest mesoxalic acid selectivity of 86.42% was obtained for Pt-Pd/CNT catalyst while a maximum tartronic acid selectivity of 50.17% and 46.02% was achieved for Pd/CNT and Pt/CNT respectively. It was found that the introduction of Pd into Pt/CNT lattice facilitated the formation of C3 products in terms of maximum selectivity achieved (86.42%) while the monometallic catalysts (Pd/CNT and Pt/CNT) showed a poor performance in comparison to their counterpart.

Loperamide Induced Life Threatening Ventricular Arrhythmia.

Loperamide is over-the-counter antidiarrheal agent acting on peripherally located µ opioid receptors. It is gaining popularity among drug abusers as opioid substitute. We report a case of a 46-year-old male that was presented after cardiac arrest. After ruling out ischemia, cardiomyopathy, pulmonary embolism, central nervous system pathology, sepsis, and other drug toxicity, we found out that patient was using around 100 mg of Loperamide to control his chronic diarrhea presumably because of irritable bowel syndrome for last five years and consumed up to 200 mg of Loperamide daily for last two days before the cardiac arrest. We hypothesize that the patient's QTc prolongation and subsequent cardiac arrest are due to Loperamide toxicity. Patient experienced gradual resolution of tachyarrhythmia and gradual decrease in QTc interval during hospitalization which supports the evidence of causal relationship between Loperamide overdose and potentially fatal arrhythmias. It also provided the clue that patient may have congenital long QT syndrome which was unmasked by Loperamide causing ventricular arrhythmias. This case adds one more pearl in the literature to support that Loperamide overdose related cardiac toxicity does exist and it raises concerns over Loperamide abuse in the community.