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Recent evidence suggests a high-sodium microenvironment in breast tumors. However, the exact role of this high-sodium microenvironment on tumorigenesis is unknown. Salt (sodium chloride, NaCl) is a well-known inflammatory molecule playing a significant role in various chronic ailments like cardiovascular and autoimmune diseases. Importantly, chronic inflammation is recognized as one of the major hallmarks of carcinogenesis. Breast cancer cell culture-based studies demonstrated that high-salt (HS) treatment (Δ35–50 mM NaCl) induced cancer cell proliferation. However, preclinical murine research showed reduced tumor progression kinetics in mice fed a short-term HS diet (4% NaCl diet, 0–2 weeks prior to the injection of tumor cells). Molecular studies demonstrated that the short-term HS diet induced the inflammatory activation of naïve CD4+ T cells to the Th17/Th1 anti-tumor phenotype. As human health-related adverse outcomes from HS diets usually occur as a consequence of prolonged HS intake over a period of several years, we have developed a novel chronic HS dietary murine tumor model. In this model, tumor cells are sequentially passaged (four cycles) in vivo under high-salt conditions, and tumor kinetics were analyzed in the passage-4 mice. These studies demonstrated enhanced tumor progression (pro-tumor) under chronic HS dietary conditions through the activation of tumor-initiating stem cells, along with the exhaustion of immune cells. Based on the, apparently paradoxical, evidence, we propose a comprehensive unifying hypothesis to elucidate the complex role of a high-sodium microenvironment towards tumor immune sculpting. This understanding will enable novel drug repositioning strategies, the development of unique ion channel-based anti-cancer therapeutics and promote low-salt diet intake in breast cancer patients on immunotherapy.

Genomic instability is one of the well-established hallmarks of cancer. The homologous recombination repair (HRR) pathway plays a critical role in correcting the double-stranded breaks (DSB) due to DNA damage in human cells. Traditionally, the BRCA1/2 genes in the HRR pathway have been tested for their association with breast cancer. However, defects in the HRR pathway (HRD, also termed ‘BRCAness’), which has up to 50 genes, have been shown to be involved in tumorigenesis and treatment susceptibility to poly-ADP ribose polymerase inhibitors (PARPis), platinum-based chemotherapy, and immune checkpoint inhibitors (ICIs). A reliable consensus on HRD scores is yet to be established. Emerging evidence suggests that only a subset of breast cancer patients benefit from ICI-based immunotherapy. Currently, albeit with limitations, the expression of programmed death-ligand 1 (PDL1) and tumor mutational burden (TMB) are utilized as biomarkers to predict the favorable outcomes of ICI therapy in breast cancer patients. Preclinical studies demonstrate an interplay between the HRR pathway and PDL1 expression. In this review, we outline the current understanding of the role of HRD in genomic instability leading to breast tumorigenesis and delineate outcomes from various clinical trials. Furthermore, we discuss potential strategies for combining HRD-targeted therapy with immunotherapy to achieve the best healthcare outcomes in breast cancer patients.

Infections with multidrug-resistant organisms (MDROs) such as Gram-negative bacteria have high morbidity and mortality with limited treatment options. Colistin, an antibiotic active against MDRO, was rarely used due to frequent adverse effects, but its use has now been recommended among adults. In this study, we determined the efficacy of colistin for the treatment of sepsis in neonates. We conducted a retrospective record review of all neonates admitted to the neonatal intensive care unit of Aga Khan University Hospital, Karachi, Pakistan, between June 2015 and June 2018, who had sepsis and received colistin by intravenous, inhalation and/or intrathecal routes. Predictors of colistin efficacy, for neonatal survival and microbial clearance, were assessed using multiple logistic regression. 153 neonates received colistin; 120 had culture-proven sepsis; and 93 had MDR-GNB (84 colistin-sensitive). 111 (72.5%) neonates survived and were discharged from hospital; 82.6% had microbial clearance. Neonates with colistin-sensitive bacteria (adjusted OR (AOR)=3.2, 95% CI 2.8 to 4.0), and those in which colistin therapy started early (AOR=7.2, 95% CI 3.5 to 13.6) were more likely to survive. Neonates with increased gestational age (AOR=1.9, 95% CI 1.5 to 3.0), higher weight (AOR=5.4, 95% CI 3.3 to 11.8) and later onset of sepsis (AOR=4.3, 95% CI 2.0 to 9.0) had higher survival. Adverse events included nephrotoxicity in 5.2%; 13.7% developed seizures and 18.3% had electrolyte imbalance. Colistin therapy was associated with survival among neonates suffering from MDR-GNB sepsis. The frequency of side effects was moderate.

Several chronic inflammatory diseases have been linked to high-salt (HS) diets. Chronic inflammation is an established causative hallmark of cancer. However, a direct role of HS diets in tumorigenesis is yet to be defined. Previous orthotopic murine breast tumor studies have shown that short-term HS diets caused inhibition of tumor growth through the activation of cytotoxic adaptive immune responses. However, there have been experimental challenges in developing a viable chronic HS-diet-based murine tumor model. To address this, we have developed a novel chronic HS diet tumor model through the sequential passaging of tumor cells in mice under HS dietary conditions. Two orthotopic murine triple-negative breast cancer models, 4T1 tumor cells injected into BALB/c mice and Py230 tumor cells injected into C57Bl/6 mice, were utilized in our study. For the HS diet cohort, prior to orthotopic injection with tumor cells, the mice were kept on a 4% NaCl diet for 2 weeks. For the regular salt (RS) diet cohort, the mice were kept on a 1% NaCl diet. Following syngeneic cancer cell injection, tumors were allowed to grow for 28 days, following which they were collected to isolate immune cell-depleted cancer cells (passage 1, P1). The tumor cells from P1 were reinjected into the next set of non-tumor-bearing mice. This procedure was repeated for three cycles (P2–P4). In P1, compared to the RS diet cohort, we observed reduced tumor kinetics in both murine tumor models on the HS diet. In contrast, by P4, there was significantly higher tumor progression in the HS diet cohort over the RS diet cohort. Flow cytometry analysis demonstrated an 8-fold increase in tumor-initiating stem cells (TISCs) from P1 to P4 of the HS diet cohort, while there were no significant change in TISC frequency with sequential passaging in the RS diet cohort. Molecular studies showed enhanced expression of TGFβR2 and CD80 on TISCs isolated from the P4 HS diet cohort. In vitro studies demonstrated that TGFβ stimulation of these TISCs increased the cellular expression of CD80 molecules. Further, the chronic HS diet selectively induced the glycolytic metabolic phenotype over the mitochondrial oxidative phosphorylation phenotype in TISCs, which is needed for the production of metabolites during tumor cell differentiation and proliferation. The infiltrating CD8 and CD4 T-lymphocytes in P4 tumors demonstrated increased expression of the immune checkpoint inhibitor (ICI) CTLA4, a known binding partner of CD80, to cause immune exhaustion and pro-tumorigenic effects. Interestingly, anti-TGFβ monoclonal antibodies (mAbs) played a synergistic role in further enhancing the anti-tumor effect of anti-CTLA4 mAb. In summary, our findings demonstrated that chronic HS diet increased the frequency of TISCs in tumors leading to blunting of cytotoxic adaptive immune responses causing tumor proliferation. Furthermore, a combination of anti-TGFβ with current ICI-based immunotherapies could exert more favorable anti-cancer clinical outcomes.

The coronavirus disease 19 (COVID-19) is rapidly spreading across the world. Pharmacy services play a vital role in public health in preventing and containing the COVID-19 pandemic. All over the world, especially in the developed countries pharmacists have responded smartly and speedily for public health, such as establishing professional protective and service guidance for pharmacy staff and services, creating and updating drug formularies, addressing the issues of drug shortages, providing public education for prevention and management of infection, contributing in drug evaluation and clinical trials. In this commentary, we review the exclusive demands from pharmacy services in Pakistan during coronavirus disease 2019 pandemic and sharing the responses of our hospital pharmacy to these demands and needs with the international pharmacy community, especially of the low and middle-income countries like Pakistan.

ABSTRACT Objective: To find the effect of dexmedetomidine on acute post-operative analgesia and on postoperative opioid requirement. Study Design: Quasi experimental study. Place and Duration of Study: The study was conducted at department of Anaesthesia and Intensive care, CMH Rawalpindi, from Jan 2015 to Oct 2015. Methodology: In this study 80 patients were divided in two equal groups. Group A was controlled group in which saline infusion was used and Group B was study group in which dexmedetomidine infusion was used. Both groups were anesthetized with similar technique and were given nalbuphine 0.1mg/kg in the beginning. Group B was started dexmedetomidine almost half hour before end of procedure and group A was given normal saline. Infusion of dexmedetomidine continued for 8 hours postoperatively. Rescue nalbuphine of 0.05mg/kg was given in both groups when visual analogue scale score was 3 or more. Results: Eighty patients including 48 (60%) males and 32 (40%) females were enrolled in study. In group A loading dose of nalbuphine was 7.02 ± 0.76 mg and in group B it was 6.93 ± 1.00 mg. Mean loading dose of dexmedetomidine was 32.98 ± 9.11µg. Mean Dexmedetomidine given in infusion was 105.56 ± 29.16 µg. There was significant decrease in VAS score in group B. In group A total postoperative nalbuphine used was 8.13 ± 2.86 mg and in dexmedetomidine group total nalbuphine used was 5.01 ± 1.93 mg. The p-value was 0.001 which was significant. Conclusion: Use of dexmedetomidine resulted in reduced acute postoperative pain as shown by better visual analogue scale profile. It also resulted in reduced opioid requirement in postoperative period. We suggest that studies should be done which also include these factors and have large sample size so results can be generalized on population.

ABSTRACT Objective: To find out whether pre-emptive thoracic epidural analgesia is superior to conventional postoperative epidural analgesia for post-thoracotomy pain. Study Design: Randomized controlled trial. Place and Duration of Study: Department of anesthesia and critical care, Combined Military Hospital Rawalpindi, from Apr 2017 to Aug 2017. Methodology: After ethical committee approval and informed consent from patients, 40 patients undergoing thoracotomy were included in study. Preoperatively thoracic epidural catheter was inserted at T7-9 intervertebral space level. Group P was given 0.1ml/kg of 0.125% bupivacaine before induction of anesthesia; whereas group C was administered 5 ml 0.125% bupivacaine after closure of wound in supine position. Visual analog scale(VAS) was used to assess pain severity at 1 and 24 hours postoperatively, both at rest and after cough(R1, R24, C1 and C24 respectively). Data were analyzed with SPSS 16. Results: There was no statistical difference in demographic profile of both groups in terms of age, gender, site of insertion of epidural catheter, American Society of Anaesthesiologists(ASA) status or type of surgery. Pain was significantly less in group P at 1hour postoperatively(p=0.009). However, there was no difference in pain severity at rest at 24 hours and with cough at 01 hour or 24 hours postoperatively. Conclusion: Preemptive thoracic epidural analgesia provides better pain control in immediate postoperative period at rest. However, its efficacy is similar to conventional epidural analgesia in immediate post op period with cough and at 24 hours with cough and at rest.

ABSTRACT Objective: To determine the frequency of malposition of left sided double lumen endotracheal tube with fiberoptic bronchoscope after its correct positioning by auscultation. Study Design: Prospective observational study. Place and Duration of Study: Main operation theater, Combined Military Hospital, Rawalpindi, from Jul 2015 to Dec 2016. Methodology: After approval from ethical review committee and consent, 90 patients with American Standards Association (ASA) II and III status were included in study by consecutive sampling. Proper monitoring attached and patients were premedicated. After induction of general anesthesia left sided double lumen tube was inserted by direct laryngoscopy. After inflation of cuffs, auscultation was done to determine correct position of tube. Then position of tube was confirmed by fiber optic bronchoscope. Results: The mean age was 38.13 ± 15.43 years and 66 (73.3%) males. In all the patients, auscultation showed that the left sided double lumentube were in the correct position with adequate ventilation of left upper and lower lobes. However, flexible bronchoscopy showed that double lumentubes had been placed correctly in only 54 (60%) cases, while 36 (40%) cases had partially misplaced double lumentubes. Out of these 36 cases, 26 (72.2%) had distally malpositioned double lumentube and 10 (27.8%) patients had proximally displaced double lumentube. Conclusion: Auscultation was found an unreliable method for confirmation of correct position of double lumentube and fibreoptic bronchoscope should be used for the confirmation of correct position of double lumentube for better anesthetic management in one lung ventilation.

Exogenous melatonin (EMT) application has been used to reduce postharvest senescence and improve the quality and antioxidant enzyme activities of papaya fruits during cold storage. The effects of exogenous melatonin application (1. 5 mM) were investigated on papaya fruits during cold storage (10°C ± 2°C) for 28 days in the present study. The EMT treatment delayed postharvest senescence significantly with lower maturing status compared with untreated papaya fruits (control). In addition, EMT treatment maintained substantially higher titratable acidity values and ascorbic acid content but significantly lower soluble solids content and lower weight loss compared with the untreated fruits. Concerning the antioxidant capacity, the EMT-treated papaya fruit exhibited markedly higher total phenolic content and, consequently, higher DPPH-radical scavenging activity than the control group. The EMT treatment not only kept a higher enzyme activity of superoxide dismutase, peroxidase, and catalase but also significantly inhibited the accumulation of hydrogen peroxide and malondialdehyde, along with satisfying sensory attributes. The findings of this study indicated that EMT application could be commercially used as an eco-friendly strategy to reduce postharvest senescence and maintain the fresh-like quality traits of papaya fruit during cold storage.

Papaya fruit has a limited shelf life due to its sensitivity to decay and chilling damage during cold storage. The application of methyl jasmonate (MeJA) is known to reduce the incidence of disease and chilling injury, and to maintain the overall quality of the papaya fruit when stored at low temperature. Consequently, the effects of postharvest MeJA (1 mM) immersion on papaya fruits during low-temperature storage (10 °C ± 2 °C) for 28 days were studied. The experiment revealed that MeJA treatment significantly decreased the papaya fruit’s weight loss, disease incidence, and chilling injury index. Furthermore, the accumulation of malondialdehyde and hydrogen peroxide was markedly lower after the application of MeJA. In addition, MeJA treatment exhibited significantly higher total phenols, ascorbic acid, antioxidant activity, and titratable acidity in contrast to the control. Similarly, MeJA-treated papaya fruits showed higher antioxidant enzymatic activity (superoxide dismutase, catalase, and peroxidase enzymes) with respect to the control fruits. In addition, MeJA reduced the soluble solids content, ripening index, pH, and sugar contents compared to the control fruits. Furthermore, MeJA-treated papaya fruit exhibited higher sensory and organoleptic quality attributes with respect to untreated papaya fruits. These findings suggested that postharvest MeJA application might be a useful approach for attenuating disease incidence and preventing chilling injury by enhancing antioxidant activities along with enhanced overall quality of papaya fruits during low-temperature storage.