The p97-UBXD8 complex maintains peroxisome abundance by suppressing pexophagy.

Peroxisomes are vital organelles involved in key metabolic functions in eukaryotic cells. Their significance is highlighted by peroxisome biogenesis disorders; severe childhood diseases marked by disrupted lipid metabolism. One mechanism regulating peroxisome abundance is through selective ubiquitylation of peroxisomal membrane proteins that triggers peroxisome degradation via selective autophagy (pexophagy). However, the mechanisms regulating pexophagy remain poorly understood in mammalian cells. Here we show that the evolutionarily conserved AAA-ATPase p97 and its membrane embedded adaptor UBXD8 are essential for maintaining peroxisome abundance. From quantitative proteomic studies we reveal that loss of UBXD8 affects many peroxisomal proteins. We find depletion of UBXD8 results in a loss of peroxisomes in a manner that is independent of the known role of UBXD8 in ER associated degradation (ERAD). Loss of UBXD8 or inhibition of p97 increases peroxisomal turnover through autophagy and can be rescued by depleting key autophagy proteins or overexpressing the deubiquitylating enzyme USP30. Furthermore, we find increased ubiquitylation of the peroxisomal membrane protein PMP70 in cells lacking UBXD8 or p97. Collectively, our findings identify a new role for the p97-UBXD8 complex in regulating peroxisome abundance by suppressing pexophagy.

Reduction of high-grade spondylolisthesis using minimally invasive spine surgery-transforaminal lumbar interbody fusion "trial-in-situ" technique: a technical note with case series.

This retrospective case series evaluated the effectiveness of minimally invasive spine surgery-transforaminal lumbar interbody fusion (MIS-TLIF) using the "trial-in-situ " technique for reducing high-grade spondylolisthesis. The surgical management of grade ≥III spondylolisthesis has been controversial, with various methods documented in the literature, including in-situ fusion, in-situ trans-sacral delta fixation, distraction techniques, and external reduction techniques. Recently, MIS techniques have gained popularity. This study analyzed 18 cases of high-grade spondylolisthesis treated with MIS-TLIF using the "trial-in-situ " technique. The clinical outcomes were assessed using the Visual Analog Scale (VAS) and the modified Oswestry Disability Index (mODI) scores. The spinopelvic parameters and sagittal balance were also analyzed. Preoperatively, the spinopelvic parameters were deranged, with a mean pelvic tilt of 28.31°, which improved to 13.91° postoperatively. Similarly, the sacral slope improved from 45.65° to 38.01°. VAS and mODI scores improved postoperatively, indicating the effectiveness of the "trial-in-situ " technique in reducing high-grade spondylolisthesis and achieving a better sagittal profile and spinopelvic parameters. The findings indicate that MIS-TLIF using the "trial-in-situ " technique is a viable and effective method for treating high-grade spondylolisthesis.

Plant plasmodesmata bridges form through ER-dependent incomplete cytokinesis.

Diverging from conventional cell division models, plant cells undergo incomplete division to generate plasmodesmata communication bridges between daughter cells. While fundamental for plant multicellularity, the molecular events leading to bridge stabilization, as opposed to severing, remain unknown. Using electron tomography, we mapped the transition from cell plate fenestrae to plasmodesmata. We show that the ER connects daughter cells across fenestrae, and as the cell plate matures, fenestrae contract, causing the PM to mold around constricted ER tubes. The ER's presence prevents fenestrae fusion, forming plasmodesmata, while its absence results in closure. The ER-PM tethers MCTP3, 4, and 6 further stabilize nascent plasmodesmata during fenestrae contraction. Genetic deletion in Arabidopsis reduces plasmodesmata formation. Our findings reveal how plants undergo incomplete division to promote intercellular communication. One-Sentence Summary: The ER is important for stabilizing nascent plasmodesmata, a process integral to incomplete cytokinesis in plants.

Bladder Adjuvant Radiation Therapy (BART): Acute and Late Toxicity From a Phase III Multicenter Randomized Controlled Trial.

PURPOSE: To report toxicity from the multicenter phase III randomized trial of Bladder Adjuvant Radiation Therapy (BART) after radical cystectomy and chemotherapy in high-risk muscle-invasive bladder cancer (MIBC). METHODS AND MATERIALS: Patients with nonmetastatic urothelial MIBC with ≥1 high-risk feature after radical cystectomy- pT3-4, pN1-3, nodal yield <10, positive margin, or ≥cT3 downstaged with neoadjuvant chemotherapy- were randomized 1:1 to observation (Obs) or adjuvant radiation therapy (RT) at 4 centers, stratified by pN stage (N0, N+) and chemotherapy (neoadjuvant, adjuvant, none). Stoma-sparing image guided intensity modulated RT 50.4 Gy in 28# was prescribed to the cystectomy bed and pelvic nodes. Acute toxicity (≤3 months of RT/randomization) and late toxicity were assessed per protocol using Common Terminology Criteria for Adverse Event v5.0. Patients progressing within 3 or 6 months of randomization were excluded from acute or late toxicity analysis, respectively. RESULTS: The BART trial enrolled 153 patients (Obs = 76, RT = 77). About half (49%) had pN+. Nearly 90% received chemotherapy (70% neoadjuvant; most commonly gemcitabine plus cisplatin). In the RT arm, 63/77 completed RT per protocol with no toxicity-related RT termination. Of the 134 patients analyzable for acute toxicity, no difference was observed in grade 3 (Obs 4.2% vs RT 1.6%, P = .34). Grade 2 effects were higher with RT (17.5% vs 1.1%, P < .001), mainly diarrhea/enteritis or proctitis. Late toxicity was analyzable for 104 patients (Obs = 57, RT = 47) with a median follow-up of 27 months. Grades 3 to 4 toxicity were about 10% (Obs 10.5% vs RT 8.4%, P = .62), and cumulative late grade 2+ toxicity was similar in both groups (17.5% vs 23.3%, P = .27). CONCLUSIONS: In the largest trial of adjuvant RT for high-risk urothelial MIBC, severe acute and late toxicity were low and similar with obervation or radiation therapy. The oncological outcomes are awaited.

Phase III randomized trial comparing neoadjuvant paclitaxel+platinum to 5-fluorouracil+platinum in esophageal/GEJ squamous cell carcinoma.

PURPOSE: Standard neoadjuvant chemotherapy (NACT) for locally advanced esophageal/gastroesophageal junction squamous cancer (LAEGSC), 5-fluorouracil (5FU)+platinum, is toxic and logistically challenging; alternative regimens are needed. PATIENTS AND METHODS: Phase III randomized open-label non-inferiority trial at Tata Memorial Center, India, in resectable LAEGSC. Patients were randomized 1:1 to three cycles of 3-weekly platinum (cisplatin 75 mg/m2 or carboplatin AUC 6) with paclitaxel 175 mg/m2 (day 1) or 5FU 1000 mg/m2 continuous infusion (days 1-4), followed by surgery. RESULTS: Between August 2014 and June 2022, we enrolled 420 patients; 210 to each arm. Significantly more patients on paclitaxel + platinum (194 (92.3%)] received all 3 chemotherapy cycles than on 5FU+platinum (170 [85.9%]), P = .009. 5FU + platinum caused more grade ≥ 3 toxicities (124 [69.7%]) than paclitaxel + platinum (97 [51.9%]), P = .001. Surgery was performed in 131 (62.4%) patients on 5FU + platinum vs 139 (66.2%) on paclitaxel + platinum, P = .415. Paclitaxel + platinum resulted in higher pathologic primary tumor clearance (33 [25.8%]) vs 17 [15%]; P = .04), and pathologic complete responses in 21.9% compared to 12.4% from 5FU + platinum, P = .053. Median OS was 27.5 months (95% CI, 18.6-43.5) from paclitaxel + platinum, which was non-inferior to 27.1 months (95% CI, 18.8-40.7) from 5FU + platinum; HR, 0.89 (95% CI, 0.72-1.09); P = .346. CONCLUSION: Neoadjuvant paclitaxel + platinum chemotherapy is safer, and results in similar R0 resections, higher pathologic tumor clearance and non-inferior survival, compared to 5FU + platinum. Paclitaxel + platinum should replace 5FU + platinum as NACT for resectable LAEGSC. CLINICAL TRIALS REGISTRY INDIA NUMBER: CTRI/2014/04/004516.

Dynamic multispectral NIR/SWIR for in vivo lymphovascular architectural and functional quantification.

Significance: Although the lymphatic system is the second largest circulatory system in the body, there are limited techniques available for characterizing lymphatic vessel function. We report shortwave-infrared (SWIR) imaging for minimally invasive in vivo quantification of lymphatic circulation with superior contrast and resolution compared with near-infrared first window imaging. Aim: We aim to study the lymphatic structure and function in vivo via SWIR fluorescence imaging. Approach: We evaluated subsurface lymphatic circulation in healthy, adult immunocompromised salt-sensitive Sprague-Dawley rats using two fluorescence imaging modalities: near-infrared first window (NIR-I, 700 to 900 nm) and SWIR (900 to 1800 nm) imaging. We also compared two fluorescent imaging probes: indocyanine green (ICG) and silver sulfide quantum dots (QDs) as SWIR lymphatic contrast agents following intradermal footpad delivery in these rats. Results: SWIR imaging exhibits reduced scattering and autofluorescence background relative to NIR-I imaging. SWIR imaging with ICG provides 1.7 times better resolution and sensitivity than NIR-I, and SWIR imaging with QDs provides nearly two times better resolution and sensitivity with enhanced vessel distinguishability. SWIR images thus provide a more accurate estimation of in vivo vessel size than conventional NIR-I images. Conclusions: SWIR imaging of silver sulfide QDs into the intradermal footpad injection provides superior image resolution compared with conventional imaging techniques using NIR-I imaging with ICG dye.

Calcium intake and genetic variants in the calcium sensing receptor in relation to colorectal cancer mortality: an international consortium study of 18,952 patients.

Background: Research on calcium intake as well as variants in the calcium sensor receptor (CaSR) gene and their interaction in relation to CRC survival is still limited. Methods: Data from 18,952 CRC patients, were included. Associations between primarily pre-diagnostic dietary (n = 13.085), supplemental (n = 11,837), total calcium intake (n = 5970) as well as 325 single nucleotide polymorphisms (SNPs) of the CaSR gene (n = 15,734) in relation to CRC-specific and all-cause mortality were assessed using Cox proportional hazard models. Also interactions between calcium intake and variants in the CaSR gene were assessed. Results: During a median follow-up of 4.8 years (IQR 2.4-8.4), 6801 deaths occurred, of which 4194 related to CRC. For all-cause mortality, no associations were observed for the highest compared to the lowest sex- and study-specific quartile of dietary (HR 1.00, 95%CI 0.92-1.09), supplemental (HR 0.97, 95%CI 0.89-1.06) and total calcium intake (HR 0.99, 95%CI 0.88-1.11). No associations with CRC-specific mortality were observed either. Interactions were observed between supplemental calcium intake and several SNPs of the CaSR gene. Conclusion: Calcium intake was not associated with all-cause or CRC-specific mortality in CRC patients. The association between supplemental calcium intake and all-cause and CRC-specific mortality may be modified by genetic variants in the CaSR gene.

Current Practices in Genetic Testing for Prostate Cancer: The Indian Scenario.

BACKGROUND: Despite genetic testing being recommended by international guidelines for the selection of targeted therapy for prostate cancer (PCa), limited data are available on genetic testing for PCa in India. OBJECTIVES: The objective is to understand the current genetic testing practice pattern for PCa in India. MATERIALS AND METHODS: A panel of 9 experts developed and validated a premeeting online questionnaire comprising 12 objective questions. The questionnaire was circulated from February 2022 to May 2022 among medical oncologists and uro-oncologists across pan-India, followed by response collection over 3 months. Descriptive statistics were used to summarize results and concluding statements were formulated on current genetic testing practice patterns for PCa. RESULTS: A total of 103 responses were received. Genetic testing was advised by 35.9% of the participants in <5% of patients with PCa. Patients with a family history of PCa (88.3%) were most commonly referred for genetic testing. Nearly half (50.2%) of the participants routinely tested for homologous recombination repair (HRR) genes; 52% used blood and tissue as the most preferred specimen for performing genetic testing and 44.7% followed the testing sequence of tumor tissue followed by blood. Major barriers to genetic testing were affordability and scarcity of genetic counselors, while a major change could be brought by making it cost-effective and improving access to medication. CONCLUSIONS: We observed a lower prescription frequency of genetic testing for the HRR gene across pan-India. Improving the quality and access to genetic testing and the availability of cost-effective-targeted therapies will aid in delivering personalized care to patients with metastatic PCa.

Prediagnostic Amino Acid Metabolites and Risk of Gout, Accounting for Serum Urate: Prospective Cohort Study and Mendelian Randomization.

OBJECTIVE: Our objective was to prospectively investigate prediagnostic population-based metabolome for risk of hospitalized gout (ie, most accurate, severe, and costly cases), accounting for serum urate. METHODS: We conducted prediagnostic metabolome-wide analyses among 249,677 UK Biobank participants with nuclear magnetic resonance metabolomic profiling (N = 168 metabolites, including eight amino acids) from baseline blood samples (2006-2010) without a history of gout. We calculated multivariable hazard ratios (HRs) for hospitalized incident gout, before and after adjusting for serum urate levels; we included patients with nonhospitalized incident gout in a sensitivity analysis. Potential causal effects were evaluated with two-sample Mendelian randomization. RESULTS: Correcting for multiple testing, 107 metabolites were associated with incidence of hospitalized gout (n = 2,735) before urate adjustment, including glycine and glutamine (glutamine HR 0.64, 95% confidence interval [CI] 0.54-0.75, P = 8.3 × 10-8; glycine HR 0.69, 95% CI 0.61-0.78, P = 3.3 × 10-9 between extreme quintiles), and glycoprotein acetyls (HR 2.48, 95% CI 2.15-2.87, P = 1.96 × 10-34). Associations remained significant and directionally consistent following urate adjustment (HR 0.83, 95% CI 0.70-0.98; HR 0.86, 95% CI 0.76-0.98; HR 1.41, 95% CI 1.21-1.63 between extreme quintiles), respectively; corresponding HRs per SD were 0.91 (95% CI 0.86-0.97), 0.94 (95% CI 0.91-0.98), and 1.10 (95% CI 1.06-1.14). Findings persisted when including patients with nonhospitalized incident gout. Mendelian randomization corroborated their potential causal role on hyperuricemia or gout risk; with change in urate levels of -0.05 mg/dL (95% CI -0.08 to -0.01) and -0.12 mg/dL (95% CI -0.22 to -0.03) per SD of glycine and glutamine, respectively, and odds ratios of 0.94 (95% CI 0.88-1.00) and 0.81 (95% CI 0.67-0.97) for gout. CONCLUSION: These prospective findings with causal implications could lead to biomarker-based risk prediction and potential supplementation-based interventions with glycine or glutamine.

Review Article on Molecular Basis of Zinc and Copper Interactions in Cancer Physiology.

Various clinical manifestations associated with measurable abnormalities of Zn and Cu in serum and tissue were determined in Cancer-Patients (CP), and therefore, these two metals are drawing more and more attention presently than ever before. Cancer is a disease of uncontrolled-abnormal-cell-division with invasion-potential which was exhibited to occur due to dys-regulation/dys-homeostasis of fundamental-biological-pathways (FBP) including antioxidant-enzyme-defense-system, anti-inflammatory and immune-systems, and DNA-damage-repair-system in the human-body resulting in generation of chronic-oxidative-stress induced DNA-damage and gene-mutations, inflammation and compromised immune-system, tumor-induced increased angiogenesis, and inhibition of apoptosis processes. Zn and Cu were recognized to be the most crucial components of FBP and imbalance in Zn/Cu ratios in CP asserted to generate chronic toxicity in human body through various mechanisms including increased chronic oxidative stress linked compromised DNA integrity and gene mutations due to malfunctioning of DNA damage repair enzymes; increased angiogenesis process due to Zn- and Cu-binding proteins metallothionein and ceruloplasmin-induced enhanced expression of tumor growth factors; and elevation in inflammatory response which was further shown to down/upregulate gene expression of multiple Zn transporter proteins leading to dys-homeostasis of intracellular Zn concentrations, and it was determined to disturb the equilibrium between cell growth and division, proliferation, differentiation, and apoptosis processes which lead to cancer progression. Moreover, Zn was reported to affect matrix metalloproteinase activity and influence immune system cells to respond differently to different cytokines and enhance immune-suppressive effects accelerating the angiogenesis, invasion, and metastasis potential in cancer. Further, the most significant use of serum Cu/Zn ratio was recommended in clinical diagnosis, prognosis, tumor stage, patient survival, and cancer follow-up studies which need further investigations to elucidate and explore their roles in cancer physiology for clinical perspective.

A comparative study of Infra patellar branch of saphenous nerve injury between vertical and horizontal portal incisions in knee arthroscopy.

Background: An Infrapatellar Branch of Saphenous Nerve (IPBSN) injury is one of the complications leading to sensory loss in the operated knee. A high incidence of IPBSN injury was reported during hamstring harvest, but there are only a few studies analyzing IPBSN injury during arthroscopy portals. However, there was a lack of randomized comparative studies comparing the incidence of IPBSN injury in horizontal and vertical portals. This study aimed to identify the overall incidence of IPBSN injury and compare the difference between vertical and horizontal portal incisions. We also aimed to observe the recovery pattern of IPBSN injuries in both groups. We hypothesize that since the portal incisions are very small, the incidence of IPBSN injury will be very low, and it will occur more in the vertical incision. Methods: After obtaining IRC approval from B&B Hospital IRC, this prospective comparative study was conducted at the AKB center for arthroscopy, sports injury, and regenerative medicine, B&B Hospital. The calculated sample size of 128 consecutive patients was included and divided into groups by the block randomization method. A total of 64 patients were allocated to both groups. Demographic data was recorded. The sensory loss along the IPBSN was examined and documented on the first postoperative day. Their recovery was documented during two weeks and three months of follow-up visits. Parametric and non-parametric tests were applied to analyze the variables. Results: IPBSN injury was seen in 12 patients (9.37 %) among 128 study participants. Five patients (7.81 %) had IPBSN injuries in the vertical group compared to seven (10.93 %) in the horizontal group. Recovery was earlier in the horizontal incision group. Conclusion: The overall incidence of IPBSN injury during the arthroscopy portal is low. They occur equally in vertical and horizontal portal incisions. The recovery of the IPBSN injury was better and earlier in the horizontal incision group.

Key Issues in Surgical Residency Education: Recommendations of the Blue Ribbon II Committee Residency Education Subcommittee.

In September 2022, a summit was convened by the American Board of Surgery (ABS) to discuss competency-based reform in surgical education. A key output of that summit was the recommendation that the prior work of the Blue Ribbon I Committee convened 20 years earlier be revived. With leadership from the American College of Surgeons (ACS) and the American Surgical Association (ASA) , the Blue Ribbon Committee (BRC) II was subsequently convened. This paper describes the output of the Residency Education Subcommittee of the BRC II Committee. The Subcommittee organized its work around prioritized themes including curriculum, assessment, and transition to practice. Top recommendations, time-based action steps, potential barriers, and required resources were detailed and vetted through group discussion, broader Committee review and critique, and subsequent refinement. Primary concluding emphases included transitioning to a competency-based training model, facilitating dynamically capable curricular reform emphasizing the digital transformation of surgical care, using predictive analytic assessment strategies to optimize training effectiveness and efficiency, and creating mentorship strategies to govern the transition from training to independent practice in an outcomes-accountable fashion. It was recognized that coordinated efforts across existing organizational structures will be required, informed by dataset integration strategies that meaningfully measure educational and related patient outcomes.

Docetaxel-oxaliplatin-capecitabine/5-fluorouracil (DOX/F) followed by docetaxel versus oxaliplatin-capecitabine/5-fluorouracil (CAPOX/FOLFOX) in HER2-negative advanced gastric cancers.

BACKGROUND: We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ). METHODS: This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue. RESULTS: Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations. CONCLUSION: FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944).

Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer.

PURPOSE: Nivolumab is approved at various doses, including 3 mg/kg, 240 mg and 480 mg flat doses at various dosing intervals. The concept of low-dose immunotherapy is gaining traction in recent years. However, there is a need to better understand the pharmacokinetics and clinical outcomes at lower doses. METHODS: Patients were either administered 40 mg flat dose or 3 mg/kg Q2W/Q3W, depending on affordability as per prevailing hospital practice. All patients were hospitalized on day 1 and pharmacokinetic samples were collected at 0, 0.5, 1.0, 6.0, 24.0, 72.0 h and day 14 following administration of the first dose of nivolumab. Plasma nivolumab levels were measured by ELISA. Patients were followed up for response and toxicity. RESULTS: Twenty five patients were included in the study. Fourteen received nivolumab at conventional dose (3 mg/kg), while 11 patients received low-dose (40 mg flat). The geometric means of dose normalized Cmax and AUC0-t were comparable between those who received conventional dose and low-dose of nivolumab (0.28 versus 0.23 µg/mL/mg and 0.0014 versus 0.0011 d/mL respectively). Nineteen patients were evaluable for response. ORR among patients who received conventional dose was 5/11 (45.5%) whereas it was 4/9 (44.4%) in the low-dose cohort. All 14 (100%) patients in conventional dosing group and 7/11 patients (63.64%) in low-dose group had treatment emergent adverse events. Grade ≥ 3 toxicities were observed in 4/14 patients in conventional dose group and none in low-dose group. CONCLUSION: Low-dose nivolumab leads to lower exposure in patients as compared with conventional dose, but low-dose was better tolerated, while response rates were comparable to conventional dose.

From bone to nanoparticles: development of a novel generation of bone derived nanoparticles for image guided orthopedic regeneration.

Bone related diseases such as osteoporosis, osteoarthritis, metastatic bone cancer, osteogenesis imperfecta, and Paget's disease, are primarily treated with pharmacologic therapies that often exhibit limited efficacy and substantial side effects. Bone injuries or fractures are primarily repaired with biocompatible materials that produce mixed results in sufficiently regenerating healthy and homogenous bone tissue. Each of these bone conditions, both localized and systemic, use different strategies with the same goal of achieving a healthy and homeostatic bone environment. In this study, we developed a new type of bone-based nanoparticle (BPs) using the entire organic extracellular matrix (ECM) of decellularized porcine bone, additionally encapsulating indocyanine green dye (ICG) for an in vivo monitoring capability. Utilizing the regenerative capability of bone ECM and the functionality of nanoparticles, the ICG encapsulated BPs (ICG/BPs) have been demonstrated to be utilized as a therapeutic option for localized and systemic orthopedic conditions. Additionally, ICG enables an in situ monitoring capability in the Short-Wave Infrared (SWIR) spectrum, capturing the degradation or the biodistribution of the ICG/BPs after both local implantation and intravenous administration, respectively. The efficacy and safety of the ICG/BPs shown within this study lay the foundation for future investigations, which will delve into optimization for clinical translation.

Assessing the degree of hepatic ischemia-reperfusion injury using physiologically based pharmacokinetic modeling of sodium fluorescein disposition in ex vivo machine-perfused livers.

Ischemia-reperfusion injury (IRI) is an intrinsic risk associated with liver transplantation. Ex vivo hepatic machine perfusion (MP) is an emerging organ preservation technique that can mitigate IRI, especially in livers subjected to prolonged warm ischemia time (WIT). However, a method to quantify the biological response to WIT during MP has not been established. Previous studies used physiologically based pharmacokinetic (PBPK) modeling to demonstrate that a decrease in hepatic transport and biliary excretion of the tracer molecule sodium fluorescein (SF) could correlate with increasing WIT in situ. Furthermore, these studies proposed intracellular sequestration of the hepatocyte canalicular membrane transporter multidrug resistance-associated protein 2 (MRP2) leading to decreased MRP2 activity (maximal transport velocity; Vmax) as the potential mechanism for decreased biliary SF excretion. We adapted an extant PBPK model to account for ex vivo hepatic MP and fit a six-parameter version of this model to control time-course measurements of SF in MP perfusate and bile. We then identified parameters whose values were likely insensitive to changes in WIT and fixed them to generate a reduced model with only three unknown parameters. Finally, we fit the reduced model to each individual biological replicate SF time course with differing WIT, found the mean estimated value for each parameter, and compared them using a one-way ANOVA. We demonstrated that there was a significant decrease in the estimated value of Vmax for MRP2 at the 30-min WIT. These studies provide the foundation for future studies investigating real-time assessment of liver viability during ex vivo MP.NEW & NOTEWORTHY We developed a computational model of sodium fluorescein (SF) biliary excretion in ex vivo machine perfusion and used this model to assess changes in model parameters associated with the activity of MRP2, a hepatocyte membrane transporter, in response to increasing warm ischemia time. We found a significant decrease in the parameter value describing MRP2 activity, consistent with a role of decreased MRP2 function in ischemia-reperfusion injury leading to decreased secretion of SF into bile.

Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.

BACKGROUND: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. METHODS: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. FINDINGS: The 3-DF joint test revealed two significant loci with p-value <5 × 10-8. Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10-3) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10-7). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10-8) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029). INTERPRETATION: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings. FUNDING: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments.

Do Uro-Oncology Day Care Procedures Need to Be Differed during COVID-19 Pandemic?-An Experience from Tertiary Cancer Care Center.

Mahendra PalBackground The SARS-CoV-2 virus pandemic has affected millions all over the world in very short span and changed the way how health care system work across the globe. It is essential to continue cancer treatment in spite of such pandemics. Various recommendations were proposed for cancer management based on risk stratification, however, in urological malignancies, day care procedures (DCPs) are a part of complete spectrum of cancer care and standard operating procedures (SOPs) for day care procedures (DCPs)in oncology is lacking at present. Materials and Methods This is an institutional review board approved retrospective observational analytical study performed in tertiary cancer care center, with aim to assess the impact of COVID-19 on Uro-oncology day care procedures (U-DCPs)in terms of changes in appointments and actual U-DCPs performed, demographic changes such as sex ratio and age wise attendance in pre and post lockdown period and to provide a SOPs to accomplishU-DCPsefficiently in pandemics. Results There was 67.89% and 68.16% reduction in total numbers of appointment and performed U-DCPs. A statistically significant difference was found in cystoscopy, intravesicalinstallation and miscellaneous UDCPs. Overall, 4.45% reduction and 4.52% increase in male and female patients underwent UDCPs respectively, M:F ratio reduced from 3.58:1 to 2.79:1 and 30% to 50% reduction in overall patient statistics in post lockdown compare to pre lockdown procedures. For various age groups there was a statistically significant change in the number for males underwent cystoscopy in (p<0.001), Intravesical therapies (p<0.001) and miscellaneous procedures(p< 0.004). Conclusion We are now coming up to the fact that effective management of healthcare system during pandemics require establishment and effective implementation of standard protocols. Routine major urological surgical care is continued using a tiered standard of protocols (SOPs) and adequate precautions. This study may provide an insight into impact of COVID-19 on UDCPs and what precautions and strategies can be institutionalized so that the patients and the health care workers remain protected from contracting infection while in performing DCPs during pandemic or similar circumstances.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.