LP-184, a Novel Acylfulvene Molecule, Exhibits Anticancer Activity against Diverse Solid Tumors with Homologous Recombination Deficiency.

Homologous recombination (HR)-related gene alterations are present in a significant subset of prostate, breast, ovarian, pancreatic, lung, and colon cancers rendering these tumors as potential responders to specific DNA damaging agents. A small molecule acylfulvene prodrug, LP-184, metabolizes to an active compound by the oxidoreductase activity of enzyme prostaglandin reductase 1 (PTGR1), which is frequently elevated in multiple solid tumor types. Prior work demonstrated that cancer cell lines deficient in a spectrum of DNA damage repair (DDR) pathway genes show increased susceptibility to LP-184. Here, we investigated the potential of LP-184 in targeting multiple tumors with impaired HR function and its mechanism of action as a DNA damaging agent. LP-184 induced elevated DNA double-strand breaks in HR deficient (HRD) cancer cells. Depletion of key HR components BRCA2 or ataxia telangiectasia mutated (ATM) in cancer cells conferred up to 12-fold increased sensitivity to the LP-184. LP-184 showed nanomolar potency in a diverse range of HRD cancer models, including prostate cancer organoids, leiomyosarcoma cell lines, and patient-derived tumor graft models of lung, pancreatic, and prostate cancers. LP-184 demonstrated complete, durable tumor regression in 10 patient-derived xenograft (PDX) models of HRD triple-negative breast cancer (TNBC) including those resistant to PARP inhibitors (PARPi). LP-184 further displayed strong synergy with PARPi in ovarian and prostate cancer cell lines as well as in TNBC PDX models. These preclinical findings illustrate the potential of LP-184 as a pan-HRD cancer therapeutic. Taken together, our results support continued clinical evaluation of LP-184 in a large subset of HRD solid tumors. SIGNIFICANCE: New agents with activity against DDR-deficient solid tumors refractory to standard-of-care therapies are needed. We report multiple findings supporting the potential for LP-184, a novel alkylating agent with three FDA orphan drug designations, to fill this void clinically: strong nanomolar potency; sustained, durable regression of solid tumor xenografts; synthetic lethality with HR defects. LP-184 adult phase IA trial to assess safety in advanced solid tumors is ongoing.

Investigating the Merits of Microfluidic Capillary Zone Electrophoresis-Mass Spectrometry (CZE-MS) in the Bottom-Up Characterization of Larger RNAs.

Established bottom-up approaches for the characterization of nucleic acids (NAs) rely on the strand-cleavage activity of nucleotide-specific endonucleases to generate smaller oligonucleotides amenable to gas-phase sequencing. The complexity of these hydrolytic mixtures calls for the utilization of a front-end separation to facilitate full mass spectrometric (MS) characterization. This report explored the merits of microfluidic capillary zone electrophoresis (CZE) as a possible alternative to common liquid chromatography techniques. An oligonucleotide ladder was initially employed to investigate the roles of fundamental analyte features and experimental parameters in determining the outcome of CZE-MS analyses. The results demonstrated the ability to fully resolve the various rungs into discrete electrophoretic peaks with full-width half-height (FWHH) resolution that was visibly affected by the overall amount of material injected into the system. Analogous results were obtained from a digestion mixture prepared by treating yeast tRNAPhe (75 nt) with RNase T1, which provided several well-resolved peaks in spite of the increasing sample heterogeneity. The regular shapes of such peaks, however, belied the fact that most of them contained sets of comigrating species, as shown by the corresponding MS spectra. Even though it was not possible to segregate each species into an individual electrophoretic peak, the analysis still proved capable of unambiguously identifying a total of 29 hydrolytic products, which were sufficient to cover 96% of the tRNAPhe's sequence. Their masses accurately reflected the presence of modified nucleotides characteristic of this type of substrate. The analysis of a digestion mixture obtained from the 364 nt HIV-1 5'-UTR proved to be more challenging. The electropherogram displayed fewer well-resolved peaks and significantly greater incidence of product comigration. In this case, fractionating the highly heterogeneous mixture into discrete bands helped reduce signal suppression and detection bias. As a result, the corresponding MS data enabled the assignment of 248 products out of the possible 513 predicted from the 5'-UTR sequence, which afforded 100% sequence coverage. This figure represented a significant improvement over the 36 total products identified earlier under suboptimal conditions, which afforded only 57% coverage, or the 83 observed by direct infusion nanospray-MS (72%). These results provided a measure of the excellent potential of the technique to support the bottom-up characterization of progressively larger NA samples, such as putative NA therapeutics and mRNA vaccines.

To study the expression of estrogen, progesterone receptor and p53 immunohistochemistry markers in subtyping endometrial carcinoma.

Background: Endometrial cancer is one of the most commonly diagnosed cancers in women worldwide. Aim and Objectives: To study the expression of estrogen receptor (ER), progesterone receptor (PR) and p53 immunohistochemistry (IHC) markers in subtyping endometrial carcinoma. Materials and Methods: A total of 100 cases of carcinoma endometrium submitted during January 2016 to October 2018 were included in our study. The ER, PR and p53 expressions were scored as per the adopted scoring system. Agreement between ER, PR and p53 IHC expression and the consensus HE diagnosis, FIGO grading and tumour staging were assessed using Chi square tests. Results: There was a statistical association between ER, PR and p53 status and tumour histologic type with a P value < 0.01. There was no statistical significance observed between ER and PR expressions and different FIGO grades. Statistical significance (P = 0.036) between p53 and different FIGO grades seen. No statistical significance was observed between ER, PR and p53 expressions and different tumour stages and tumour invasiveness. There was a statistical association between ER and PR status and lymph node metastasis. p53 did not show a statistical significance. Conclusion: Combination of ER, PR and p53 IHC markers can be used to distinguish type 1 and type 2 endometrial cancers. PR expression is more specific than ER in endometrioid carcinomas. p53 expression is more specific in serous carcinoma, however, p53 IHC alone cannot be used to distinguish different grades of endometrioid carcinomas as there is variability of staining in endometrioid carcinomas.

Predictors of Emotional Prosody Identification by School-Age Children With Cochlear Implants and Their Peers With Normal Hearing.

OBJECTIVES: Children with cochlear implants (CIs) vary widely in their ability to identify emotions in speech. The causes of this variability are unknown, but this knowledge will be crucial if we are to design improvements in technological or rehabilitative interventions that are effective for individual patients. The objective of this study was to investigate how well factors such as age at implantation, duration of device experience (hearing age), nonverbal cognition, vocabulary, and socioeconomic status predict prosody-based emotion identification in children with CIs, and how the key predictors in this population compare to children with normal hearing who are listening to either normal emotional speech or to degraded speech. DESIGN: We measured vocal emotion identification in 47 school-age CI recipients aged 7 to 19 years in a single-interval, 5-alternative forced-choice task. None of the participants had usable residual hearing based on parent/caregiver report. Stimuli consisted of a set of semantically emotion-neutral sentences that were recorded by 4 talkers in child-directed and adult-directed prosody corresponding to five emotions: neutral, angry, happy, sad, and scared. Twenty-one children with normal hearing were also tested in the same tasks; they listened to both original speech and to versions that had been noise-vocoded to simulate CI information processing. RESULTS: Group comparison confirmed the expected deficit in CI participants' emotion identification relative to participants with normal hearing. Within the CI group, increasing hearing age (correlated with developmental age) and nonverbal cognition outcomes predicted emotion recognition scores. Stimulus-related factors such as talker and emotional category also influenced performance and were involved in interactions with hearing age and cognition. Age at implantation was not predictive of emotion identification. Unlike the CI participants, neither cognitive status nor vocabulary predicted outcomes in participants with normal hearing, whether listening to original speech or CI-simulated speech. Age-related improvements in outcomes were similar in the two groups. Participants with normal hearing listening to original speech showed the greatest differences in their scores for different talkers and emotions. Participants with normal hearing listening to CI-simulated speech showed significant deficits compared with their performance with original speech materials, and their scores also showed the least effect of talker- and emotion-based variability. CI participants showed more variation in their scores with different talkers and emotions than participants with normal hearing listening to CI-simulated speech, but less so than participants with normal hearing listening to original speech. CONCLUSIONS: Taken together, these results confirm previous findings that pediatric CI recipients have deficits in emotion identification based on prosodic cues, but they improve with age and experience at a rate that is similar to peers with normal hearing. Unlike participants with normal hearing, nonverbal cognition played a significant role in CI listeners' emotion identification. Specifically, nonverbal cognition predicted the extent to which individual CI users could benefit from some talkers being more expressive of emotions than others, and this effect was greater in CI users who had less experience with their device (or were younger) than CI users who had more experience with their device (or were older). Thus, in young prelingually deaf children with CIs performing an emotional prosody identification task, cognitive resources may be harnessed to a greater degree than in older prelingually deaf children with CIs or than children with normal hearing.

Rapid characterization of adeno-associated virus (AAV) capsid proteins using microchip ZipChip CE-MS.

Adeno-associated viruses (AAVs) are viral vectors used as delivery systems for gene therapies. Intact protein characterization of AAV viral capsid proteins (VPs) and their post-translational modifications is critical to ensuring product quality. In this study, microchip-based ZipChip capillary electrophoresis-mass spectrometry (CE-MS) was applied for the rapid characterization of AAV intact VPs, specifically full and empty viral capsids of serotypes AAV6, AAV8 and AAV9, which was accomplished using 5 min of analysis time. Low levels of dimethyl sulfoxide (4%) in the background electrolyte (BGE) improved MS signal quality and component detection. A sensitivity evaluation revealed consistent detection of VP proteoforms when as little as 2.64 × 106 viral particles (≈26.4 picograms) were injected. Besides the traditional VP proteoforms used for serotype identification, multiple VP3 variants were detected, including truncated VP3 variants most likely generated by leaky scanning as well as unacetylated and un-cleaved VP3 proteoforms. Phosphorylation, known to impact AAV transduction efficiency, was also seen in all serotypes analysed. Additionally, low abundant fragments originating from either N- or C-terminus truncation were detected. As the aforementioned VP components can impact product quality and efficacy, the ZipChip's ability to rapidly characterize them illustrates its strength in monitoring product quality during AAV production.

Emotional prosody perception and production are linked in prelingually deaf children with cochlear implantsa).

Links between perception and production of emotional prosody by children with cochlear implants (CIs) have not been extensively explored. In this study, production and perception of emotional prosody were measured in 20 prelingually deaf school-age children with CIs. All were implanted by the age of 3, and most by 18 months. Emotion identification was well-predicted by prosody productions in terms of voice pitch modulation and duration. This finding supports the idea that in prelingually deaf children with CIs, production of emotional prosody is associated with access to auditory cues that support the perception of emotional prosody.

Rapid Intact Mass Analysis and Evaluation of the Separation Potential of Microfluidic Capillary Electrophoresis Mass Spectrometry for Oligonucleotides.

Oligonucleotide characterization is a rapidly advancing field in the biopharmaceutical industry. Understanding critical quality attributes, such as intact mass and impurities, requires a toolbox of analytical techniques, which commonly includes liquid chromatography-mass spectrometry (LC-MS). Oligonucleotide LC-MS analysis frequently requires sample run times upward of 15 min to achieve separation of multiple oligonucleotide species. Additionally, LC methods frequently employ mobile phase additives such as triethylamine and 1,1,1,3,3,3-hexafluoro-2-propanol that are not always desired for use in MS instrumentation. Here, microfluidic capillary electrophoresis mass spectrometry (CE-MS) via ZipChip technology was employed to enable rapid intact mass analysis of oligonucleotide single strands. Baseline separation of equal length oligonucleotides was achieved in less than 4 min. Additionally, the potential of the ZipChip platform for separation of oligonucleotide full-length products (FLPs) and their impurities was evaluated.

Evaluating the role of the Minimal Incision Retroperitoneal Necrosectomy (MIRN) in the management of infected pancreatic necrosis: Experience from a tertiary care center.

Background: The conventional open necrosectomy was associated with high mortality and morbidities like secondary organ failure, incisional hernia, enterocutaneous fistula, and external pancreatic fistula. In acute pancreatitis, collections are primarily confined to the retroperitoneal space. Hence, the retroperitoneal approach can be used to drain the collection and necrotic material. It benefits smaller incisions and better outcomes in terms of morbidity and mortality than the conventional open necrosectomy. This study primarily aims to describe the effects of minimal incision retroperitoneal necrosectomy versus conventional open necrosectomy for treating INP. Moreover, it provides evidence supporting the efficacy and safety of this method. Methods: A single-center retrospective study of the prospectively maintained database from April 2008 to December 2021. Results: A total of 122 patients were included in the study. Seventy-eight patients had an open necrosectomy, 30 had a MIRN, and 14 had a VARD procedure. These three groups were comparable in demographic variables. Preoperative variables like APACHE II at presentation, Modified CTSI, percentage of necrosis, multi-organ failure, time to surgery, and need for preoperative ICU stay were comparable among the three groups. Postoperative mortality was low in the MIRN group{open 35.8 % vs. MIRN 20.5 % vs. VARD 35.7 %, p = 0.066}. The postoperative stay was also significantly low in the MIRN and VARD group {open 23.62 ± 16.61 vs. MIRN 11.77 ± 7.73, VARD 8.86 ± 2.98, p = 0.00}. No significant difference in re-intervention rate, postoperative bleeding, and enterocutaneous fistula. Conclusion: MIRN is a simple and easy-to-adapt procedure for infected pancreatic necrosis in the appropriately selected patient group.

Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies.

The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways. Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared with DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1, and BRCA2. Depletion of PTGR1, however, completely abrogates the antitumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy. Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184.

Preclinical Efficacy of LP-184, a Tumor Site Activated Synthetic Lethal Therapeutic, in Glioblastoma.

PURPOSE: Glioblastoma (GBM) is the most common brain malignancy with median survival <2 years. Standard-of-care temozolomide has marginal efficacy in approximately 70% of patients due to MGMT expression. LP-184 is an acylfulvene-derived prodrug activated by the oxidoreductase PTGR1 that alkylates at N3-adenine, not reported to be repaired by MGMT. This article examines LP-184 efficacy against preclinical GBM models and identifies molecular predictors of LP-184 efficacy in clinical GBM. EXPERIMENTAL DESIGN: LP-184 effects on GBM cell viability and DNA damage were determined using cell lines, primary PDX-derived cells and patient-derived neurospheres. GBM cell sensitivities to LP-184 relative to temozolomide and MGMT expression were examined. Pharmacokinetics and CNS bioavailability were evaluated in mice with GBM xenografts. LP-184 effects on GBM xenograft growth and animal survival were determined. Machine learning, bioinformatic tools, and clinical databases identified molecular predictors of GBM cells and tumors to LP-184 responsiveness. RESULTS: LP-184 inhibited viability of multiple GBM cell isolates including temozolomide-resistant and MGMT-expressing cells at IC50 = approximately 22-310 nmol/L. Pharmacokinetics showed favorable AUCbrain/plasma and AUCtumor/plasma ratios of 0.11 (brain Cmax = 839 nmol/L) and 0.2 (tumor Cmax = 2,530 nmol/L), respectively. LP-184 induced regression of GBM xenografts and prolonged survival of mice bearing orthotopic xenografts. Bioinformatic analyses identified PTGR1 elevation in clinical GBM subtypes and associated LP-184 sensitivity with EGFR signaling, low nucleotide excision repair (NER), and low ERCC3 expression. Spironolactone, which induces ERCC3 degradation, decreased LP-184 IC50 3 to 6 fold and enhanced GBM xenograft antitumor responses. CONCLUSIONS: These results establish LP-184 as a promising chemotherapeutic for GBM with enhanced efficacy in intrinsic or spironolactone-induced TC-NER-deficient tumors.

LP-284, a small molecule acylfulvene, exerts potent antitumor activity in preclinical non-Hodgkin's lymphoma models and in cells deficient in DNA damage repair.

Despite advances in therapies treating non-Hodgkin's lymphoma (NHL), 20~40% of patients experience relapsed or refractory disease. While solid tumors with homologous recombination deficiencies have been successfully targeted with synthetic lethal agents such as poly-ADP ribose polymerase (PARP) inhibitors, such synthetic lethality strategy has not yet been approved to treat patients with NHL. Here we investigated the mechanism of action (MoA) and therapeutic potential of a new-generation acylfulvene compound, LP-284, in both in vitro and in vivo NHL models. One of LP-284's MoA includes inducing the repair of double-strand DNA break (DSB). We found that LP-284 exerts nanomolar potency in a panel of hematological cancer cell lines including fifteen NHL cell lines. In vivo, LP-284 treatment prolongs the survival of mantle cell lymphoma (MCL) cell line JeKo-1 derived xenograft mice by two-fold and shows increased efficacy over bortezomib and ibrutinib. In addition, LP-284 is capable of inhibiting tumor growth of JeKo-1 xenografts that are refractory to bortezomib or ibrutinib. We further showed that LP-284 is particularly lethal in cells with deficient DNA damage response and repair, a targetable vulnerability in NHL.

AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model.

Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) from ATP and GTP. 2'3'-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates the STING pathway by hydrolyzing 2'3'-cGAMP. It has been established that the cGAS-STING pathway plays a major role in inhibiting tumor growth by upregulating T cell response. Herein, we demonstrate that AVA-NP-695, a selective and highly potent ENPP1 inhibitor, apart from the immunomodulatory effect also modulates cancer metastasis by negatively regulating epithelial-mesenchymal transition (EMT). We established that the combined addition of 2'3'-cGAMP and AVA-NP-695 significantly abrogated the transforming growth factor beta (TGF-ꞵ)-induced EMT in MDA-MB-231 cells. Finally, results from the in vivo study showed superior tumor growth inhibition and impact on tumor metastasis of AVA-NP-695 compared to Olaparib and PD-1 in a syngeneic 4T1 breast cancer mouse model. The translation of efficacy from in vitro to in vivo 4T1 tumor model provides a strong rationale for the therapeutic potential of AVA-NP-695 against triple-negative breast cancer (TNBC) as an immunomodulatory and anti-metastatic agent.

Fetal phenotypes of Mendelian disorders: A descriptive study from India.

OBJECTIVE: Exome sequencing (ES)-based diagnosis of Mendelian diseases in the fetus is limited by paucity of phenotypic information. This study reports the comprehensive phenotypes of some fetuses with Mendelian disorders. METHODS: Next generation technology-based sequencing of all coding regions of the genome (Exome sequencing) or targeted gene sequencing using Sanger or next generation platforms was performed in a cohort of deeply phenotyped, cytogenetically normal fetuses with morphological defects. Prenatal ultrasonographic phenotypes and postmortem details including dysmorphology, histopathology, and radiography were ascertained. Novel candidate genes, novel/unusual findings, and unusual genotypes in cases with confirmed Mendelian disorders are described. RESULTS: Of the 102 fetuses sequenced, 45 (44%) achieved definitive diagnosis of a Mendelian disorder with 50 pathogenic/likely pathogenic variants. The majority (87%) were autosomal recessive, 69% families were consanguineous, and 54% variants were novel. Dysmorphic syndromes, skeletal dysplasias, and metabolic disorders were the commonest disease categories, ciliopathies and dystroglycanopathies, commonest molecular categories. We describe the first fetal description of six monogenic diseases, and nine cases with novel histological findings. Nineteen cases had novel/unusual findings. CONCLUSION: This cohort demonstrates how deep fetal phenotypes of some Mendelian disorders can show novel/unusual findings, which have important implications for prenatal diagnosis of these conditions.

Decoding placental pathology: Usage of a comprehensive checklist and scoring system for reporting of placentas in the hypertensive disorders of pregnancy.

Introduction/Context: Hypertensive disorders of pregnancy (HDP) are major complications of pregnancy and seen in about 5% to 10% of all pregnancies. Among these, pre-eclampsia is a leading cause of perinatal and fetal morbidity and mortality. It is a multifactorial and multisystemic disorder that results in a variety of histomorphologic features, some of which may be missed if a diligent examination is not performed. Aims and Objectives: The present study aimed to propose a checklist and novel scoring system to ensure comprehensive placental examination. We also aimed to evaluate the correlation, if any, between histopathological and morphometric findings in HDP and with fetal growth. Materials and Methods: A total of 100 placentas of women diagnosed with hypertensive disorders of pregnancy were included in our cross-sectional, observational study. Morphometric features and histological features that are known to be seen in HDP were analyzed, and each of them was given a numerical score based on their severity. Statistical Analysis Used: Pearson correlation coefficient test was applied to correlate these findings, and ANOVA test was used to assess the correlation of these findings with fetal growth restriction (FGR). Results: More than 50% of the placentas studied recorded maximum scores for weight and volume. At least 25% of the placentas showed the presence of all histo-pathological features under study. The association of total morphometric and histological scores was not found to be statistically significant (P-value = 0.239). We found a significant difference between means of morphometric scores of cases with normal fetal growth and cases showing FGR (P-value = 0.008). Conclusion: Uneven distribution and presentation of the lesions in these cases may lead to the absence of correlation between morphometry and histopathology, as seen in our study. Morphometric derangements in the placenta correlate with FGR. Our proposed checklist and scoring system can be utilized to standardize reporting of placental specimens in the evaluation of placentas with HDP, in order to facilitate and standardize the placental reporting.

Robot-assisted versus video-assisted thoraco-laparoscopic McKeown's esophagectomy for esophageal cancer: a propensity score-matched analysis of minimally invasive approaches.

Minimally invasive esophagectomy for esophageal cancer decreases overall complication rate and leads to faster postoperative recovery. Robot-assisted minimally invasive esophagectomy is becoming more common. Its three-dimensional view and wristed instruments may provide advantages over traditional thoraco-laparoscopic techniques. There are limited studies comparing robotic and conventional thoraco-laparoscopic esophagectomy. This study aimed to evaluate short-term outcomes of robot-assisted McKeown esophagectomy (RAME) and video-assisted McKeown esophagectomy (VAME). All consecutive patients undergoing minimally invasive McKeown esophagectomy for middle and distal third esophageal cancer between January 2016 and December 2018 at our center were included in this study. Data on baseline characteristics, pathological data and short-term outcomes were collected in a dedicated database. Postoperative complications were defined as per recommendations of Esophagectomy Complications Consensus Group. Histopathologic assessment was performed as per College of American Pathologists guidelines. Propensity score matching was performed for comparison between RAME and VAME groups using age, gender, performance status, American Society of Anesthesiologists grade, body mass index, Charlson Index, tumor location, clinical tumor stage, and neoadjuvant treatment as covariates. A total of 74 patients were included, 25 of whom underwent RAME and 49 underwent VAME. Propensity score matching on 1:1 basis produced 25 pairs of patients, comparable in terms of baseline characteristics. Total operative time and estimated blood loss was similar between the two groups. Length of hospital stay was significantly lower in RAME group. Major postoperative complications (Clavien-Dindo grade ≥ 3A) were more common in VAME group, but not statistically significant. Median number of harvested lymph nodes and R0 resection rate did not differ in between the two groups. In our experience, robot-assisted McKeown esophagectomy was comparable to video-assisted McKeown esophagectomy in terms of safety, feasibility and oncologic adequacy. Use of the robot was associated with reduced hospital stay. Further randomized controlled studies with larger patient samples are needed to compare the two.

Fetal presentation of chondrodysplasia with joint dislocations, GPAPP type, caused by novel biallelic IMPAD1 variants.

Biallelic IMPAD1 pathogenic variants leads to deficiency of GPAPP (Golgi 3-prime phosphoadenosine 5-prime phosphate 3-prime phosphatase) protein and clinically causes chondrodysplasia, which is characterized by short stature with short limbs, craniofacial malformations, cleft palate, hand and foot anomalies, and various radiographic skeletal manifestations. Here we describe prenatal presentation of GPAPP deficiency caused by novel biallelic pathogenic variants, 2 base pair duplication in exon 2 of IMAPD1 gene in a patient of Asian-Indian origin. Further we report on diagnostic clues of prenatal presentation of GPAPP deficiency through ultrasonography, fetal MRI, and postmortem findings. We also provide evidence of pathophysiology of underlying GPAPP deficiency in the form of disorganization and dysplastic chondrocytes and reduced sulfation of glycoproteins through histopathology of cartilage similar to that described in mice IMPAD1 homozygous mutant model.

Tinospora Cordifolia (Giloy)-Induced Liver Injury During the COVID-19 Pandemic-Multicenter Nationwide Study From India.

Tinospora cordifolia (Giloy) is an herbal supplement commonly used in the Indian alternative medicine system Ayurveda. This herb has been promoted to the public in India as an immune booster to prevent novel coronavirus disease 2019. However, small reports have recently shown an association between Giloy use and the development of herb-induced liver injury (HILI) with autoimmune features in some patients. This large retrospective Indian multicenter study spanning 13 centers at nine locations was designed to identify features and outcomes of HILI temporally associated with Giloy use. Chemical and toxicological analyses of retrieved Giloy samples using state-of-the-art methods were also performed. We report 43 patients, of whom more than half were female, with a median time from initial Giloy consumption to symptom onset of 46 days. Patients presented with acute hepatitis, acute worsening of chronic liver disease (CLD, the most common clinical presentation), or acute liver failure. Causality assessment revealed probable liver injury in 67.4%. The most common autoantibody detected was anti-nuclear antibody. Liver biopsy in a subset revealed HILI associated with autoimmune features and hepatocyte and canalicular cholestasis and neutrophilic and eosinophilic infiltration. Conclusion: Giloy is associated with acute hepatitis with autoimmune features and can unmask autoimmune hepatitis (AIH) in people with silent AIH-related CLD. Further studies on the safety (and efficacy) of untested but heavily promoted herbals in alternative systems of medicine are an unmet need in the interests of public health and are especially important during this global health emergency.

Fluorescent organo-antimony compounds as precursors for syntheses of redox-active trimeric and dimeric alkali metal antimonides: an insight into electron transfer reduction processes.

(Tip)2SbCl (1, Tip = 2,4,6-triisopropylphenyl) has been utilized as a precursor for the synthesis of the distibane (Tip)4Sb2 (4) via one-electron reduction using KC8. The two-electron reduction of 1 and 4 afforded the novel trinuclear antimonide cluster [K3((Tip)2Sb)3(THF)5] (6). Changing the reducing agent from KC8 to a different alkali metal resulted in the solid-state isolation of corresponding stable dimeric alkali metal antimonides with the general formula [M2((Tip)2Sb)2(THF)p-x(tol)x] (M = Li (14), Na (15), Cs (16)). In this report, different aspects of the various reducing agents [K metal, KC8, and [K2(Naph)2(THF)]] used have been studied, correlating the experimental observations with previous reports. Additional reactivity studies involving 1 and AgNTf2 (Tf = trifluoromethanesulfonyl) afforded the corresponding antimony cation (Tip)2Sb+NTf2- (19). The Lewis acidic character of 19 has been unambiguously proved via treatment with Lewis bases to produce the corresponding adducts 20 and 21. Interestingly, the precursors 1 and 4 have been observed to be highly luminescent, emitting green light under short-wavelength UV radiation. All the reported compounds have been characterized via NMR, UV-vis, mass spectrometry, and single-crystal X-ray diffraction analysis. Cyclic voltammetry (CV) studies of 1 in THF showed possible two electron reduction, suggesting the in situ generation of the corresponding radical-anion intermediate 1˙- and its subsequent conversion to the monomeric intermediate (Tip)2Sb- (5) upon further reduction. 5 undergoes oligomerization in the solid state to produce 6. The existence of 1˙- was proved using electron paramagnetic resonance (EPR) spectroscopy in solution. CV studies of 6 suggested its potential application as a reducing agent, which was further proved via the conversion of Tip-PCl2 to trimeric (Tip)3P3 (17), and cAACP-Cl (cAAC = cyclic alkyl(amino)carbene) to (cAAC)2P2 (18) and 4, utilizing 6 as a stoichiometric reducing agent.

Short-term and pathologic outcomes of robotic versus open pancreatoduodenectomy for periampullary and pancreatic head malignancy: an early experience.

Open pancreatoduodenectomy (OPD) is associated with high perioperative morbidity. Adoption of robot-assisted pancreatoduodenectomy (RAPD) has been slow despite ergonomic advantages, improved visualization and dexterity. We aim to report our experience comparing operative and short-term outcomes following RAPD and OPD. We did retrospective analysis of prospectively maintained database, including all consecutive patients who underwent RAPD or OPD between January 2016 and August 2019. 48 patients were included, 21 in RAPD group and 27 in OPD group. RAPD was associated with longer mean operative time (440 vs. 414.1 min) but had significantly less mean intra-operative blood loss (256.9 vs. 404.5 ml), median length of ICU stay (1 vs. 3 days), overall length of stay (11 vs. 13 days) and lower rates of SSI (23.8% vs. 63%). Both groups showed equal incidence of POPF, comparable R0 resection rates (100% vs. 96.3%) and median number of lymph nodes harvested (14 vs. 18). Rate of open conversion was 28.6% (n = 6), most commonly for bleeding (66.6%) and mesenteric vessel involvement (33.3%). When compared to first ten RAPD cases, mean operative time (483.5 vs. 400.5 min) and rate of conversion (36.36% vs. 20%) was less in last eleven cases. RAPD is significantly better than OPD in terms of intra-operative blood loss, length of ICU stay, length of total stay and SSI. The longer operative time and conversion rate associated with RAPD progressively decreased as experience accumulated and the learning curve was crossed. Further randomized controlled trials are needed to investigate cost-effectiveness and long-term oncologic survival in RAPD patients.