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  • PM condemns storming of Al-Aqsa mosque by Israeli ministers, settler groups – RADIO PAKISTAN

    1. PM condemns storming of Al-Aqsa mosque by Israeli ministers, settler groups  RADIO PAKISTAN
    2. Israeli minister sparks anger by praying at sensitive Jerusalem holy site  BBC
    3. Israel-Gaza war: anger grows over Israeli far-right minister praying at al-Aqsa mosque – as it happened  The Guardian
    4. Israel’s Ben-Gvir says he prayed at Al-Aqsa mosque compound  Reuters
    5. Far-right Israeli minister prays at Jerusalem’s most sensitive holy site, breaching decades-old agreement  CNN

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  • Someone has decided to fold the Galaxy Z Fold 7 200,000 times

    Someone has decided to fold the Galaxy Z Fold 7 200,000 times

    Ryan Haines / Android Authority

    TL;DR

    • A YouTuber is currently folding and unfolding the Galaxy Z Fold 7 live on YouTube.
    • The phone has already survived over 100,000 folds.
    • The goal of the YouTuber is to manually fold the device 200,000 times and see if it survives.

    A Korean tech YouTuber is currently putting the Samsung Galaxy Z Fold 7 through an extreme durability test, folding and unfolding it live on YouTube with a goal of hitting 200,000 folds. Yes, by hand. And no, we don’t recommend trying this at home unless you have a lot of patience (and nothing better to do for several days). Honestly, it’s kind of nice that the YouTuber is doing the hard work so the rest of us don’t have to.

    How’s the Galaxy Z Fold 7 holding up?

    As of writing this, the fold count has reached 113,368, meaning the YouTuber is likely a day or so away from reaching the 200,000 mark. It’s worth noting that Samsung officially rates the Z Fold 7’s internal OLED panel for up to 500,000 folds under ideal conditions. Still, manually folding it that many times might take over a week and probably the YouTuber’s sanity. Aiming for 200,000 folds seems like a more reasonable target.

    Along the way, the YouTuber is pausing at certain milestones to check how the phone is doing. At 95,000 folds, everything appeared normal. The display was rendering colors correctly, touch sensitivity was intact, and components like the speakers were working fine.

    After hitting 100,000 folds, a slight crackling sound began to appear while opening and closing the phone. Despite the noise, the inner display continued to function without flickering or visible damage.

    By 105,021 folds, the screen was still fully functional, although the crease had become noticeably deeper.

    Will it make it to 200,000? We think so. Samsung has used a 50% thicker Ultra Thin Glass (UTG) layer on the inner display of the Fold 7 to improve shock absorption. There’s also a new high-elastic adhesive that binds the OLED layers and, as per Samsung, offers four times the recovery performance compared to previous materials. Moreover, a high-strength titanium plate backs the screen. With all this, and the lab results previously provided by Samsung, we feel the Fold 7 should survive the YouTuber’s test.

    However, since the fold test is being done manually and not in controlled lab conditions, it should give us a more realistic idea of how repeated folding affects the device in everyday use.

    If you’re curious, you can still catch the livestream and see how the phone performs in real time.

    Thank you for being part of our community. Read our Comment Policy before posting.

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  • Liver cancer crisis looming as prevention lags, says Lancet report

    Liver cancer crisis looming as prevention lags, says Lancet report

    A new report from The Lancet reveals that three out of five liver cancer cases worldwide are linked to preventable risk factors, with obesity-related cases on the rise.

    The analysis, published on 29th July, estimates that over 60% of liver cancers could be avoided by addressing viral hepatitis, excessive alcohol consumption, and metabolic dysfunction-associated steatotic liver disease (MASLD), a condition driven by excess fat in the liver.

    Without urgent intervention, the number of new liver cancer cases is projected to nearly double by 2050, reaching 1.52 million annually, with deaths rising from 760,000 to 1.37 million in the same period.

    The situation is particularly urgent in Africa where liver cancer cases are projected to surge significantly by 2050.

    The Lancet Commission on liver cancer warns that MASLD, particularly its severe form, metabolic dysfunction-associated steatohepatitis (MASH), is the fastest-growing cause of liver cancer, expected to increase by 35% by 2050.

    One of the commissioning authors of the report, Professor Hashem El-Serag, a hepatologist at Baylor College of Medicine, believes liver cancer has a perception issue and isn’t being taken seriously enough.

    Rising obesity rates in the U.S., Europe, and Asia are fuelling this trend, with over 55% of U.S. adults predicted to develop MASLD by 2040.

    The situation is similar in Africa where refined sugars and unhealthy diets are becoming increasingly common.

    In Africa in particular Dr Kalebi believes there is less stigma around obesity and that a “pot belly” has cultural links with wealth and prosperity.

    But he makes a link between diet and poverty and believes this is driving much of the rise.

    He says: “Metabolic liver disease or metabolic symptoms in general is actually becoming a poor man’s disease because the people who are poor are the most affected by poor diet because they are taking unhealthy foods. So unhealthy foods are actually becoming a bigger problem among the poor in the third world, in the rural areas because they are not aware. So somebody takes Fanta and Coke with bread for lunch, which is very unhealthy. It used to be seen that these kinds of foods are a sign of affluence, It used to be seen that a pot belly or weight is a sign of affluence, it is actually the other way round. We need to change that narrative.”

    Meanwhile, cases linked to hepatitis B and C are projected to decline slightly due to vaccination and treatment efforts.

    The Commission calls for global action to curb preventable liver cancer, including expanded hepatitis B vaccination, stricter alcohol policies, and early screening for high-risk groups such as individuals with obesity and diabetes.

    If countries reduce liver cancer incidence by 2-5% annually, up to 17 million cases and 15 million deaths could be prevented by 2050.

    Professor Hashem El-Serag believes cases of Hepatitis B and C are what is causing the increased liver cancer rates in Africa and that screening and vaccination in the region is lagging behind the rest of the world.

    However, he stresses obesity – as the continent becomes increasingly ‘westernised’ is also a major factor.

    “Africa is also not immune to the obesity epidemic. With the progressive westernisation of their lifestyle and their diets. So they might be hit with multiple risk factors. A leftover from the old risk factors that really are not moving fast enough. And the emergence of the new risk factors that are happening as a result of globalization,” he says.

    Additional measures include public awareness campaigns, improved early detection, and better integration of palliative care for patients.

    With liver cancer already the sixth most common cancer and third leading cause of cancer deaths worldwide, experts stress that targeted prevention strategies could significantly alter its trajectory.

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  • The Sturgeon Moon rises, followed by the Moon’s tour of the Solar System planets. Here’s how to see it

    The Sturgeon Moon rises, followed by the Moon’s tour of the Solar System planets. Here’s how to see it

    This week, the Sturgeon Moon rises, giving moongazers across the world the chance to see a beautiful full Moon skimming the horizon.

    The Sturgeon Moon is the August full Moon, the eighth full Moon of the year, and rises on 9 August at 21:13 BST.

    What’s more, the Sturgeon Moon marks the beginning of a lunar meeting with the Solar System planets, the Moon tracking eastwards across the sky night after night and encountering Saturn, Jupiter, Venus and Mercury.

    Get weekly stargazing advice by signing up to our e-newsletter and subscribing to our YouTube channel

    Sturgeon Moon above Cefalà Diana by Dario Giannobile, 1 August 2023

    Why Sturgeon Moon?

    The term ‘Sturgeon Moon’ is one of many nicknames given to monthly full Moons, which reflect key changes or events in nature occurring during the month in question.

    August’s full Moon is known as the Sturgeon Moon because this is the time of year when sturgeon fish were most plentiful and easiest to catch in the Great Lakes of North America.

    The name reflects both the ecological cycle – as sturgeon would come into shallower waters in August – and the cultural importance of the fish as a food source in North America.

    The Sturgeon full moon rises behind Istanbul's Camlica Mosque on 1 August 2023 in Istanbul, Turkey. Photo by Chris McGrath/Getty Images
    The Sturgeon full moon rises behind Istanbul’s Camlica Mosque on 1 August 2023 in Istanbul, Turkey. Photo by Chris McGrath/Getty Images

    Other names for the August full Moon are Lynx Moon, Grain Moon and Corn Moon.

    It’s important to remember, however, that these nicknames don’t indicate the full Moon will look different to any other full Moon of the year.

    Nevertheless, full Moon names are a reminder of the changing of the seasons and the importance placed on the phases of the Moon by various cultures throughout history.

    A big, bright Moon close to foreground objects looks massive. This is the Moon illusion. Credit: Christine Rose Photography / Getty Images
    A big, bright Moon close to foreground objects looks massive. This is the Moon illusion. Credit: Christine Rose Photography / Getty Images

    Observing the 2025 Sturgeon Moon

    The Sturgeon Moon rises in the southeast around 9pm, although the exact timing will depend on your location.

    It will then set in the southwest after sunrise the following morning, 10 August.

    The Sturgeon Moon is located in the constellation Aquarius, and won’t rise very high above the horizon.

    That means there’ll be a chance to observe a phenomenon known as the Moon illusion, whereby the Moon looks enormous when it’s close to the horizon.

    This is an optical illusion: the Moon is in reality no bigger than when you observe it high up in the sky.

    Take a look at the Sturgeon Moon. Does it look huge to you?

    Full Moon is also a good time to observe features known as lunar rays.

    For more info, read our guide on how to make the most of a full Moon.

    Crater Tycho, as seen by the Hubble Space Telescope. Credit: NASA, ESA, and D. Ehrenreich (Institut de Planétologie et d'Astrophysique de Grenoble (IPAG)/CNRS/Université Joseph Fourier)
    Crater Tycho and its famous ejecta rays, as seen by the Hubble Space Telescope. Credit: NASA, ESA, and D. Ehrenreich (Institut de Planétologie et d’Astrophysique de Grenoble (IPAG)/CNRS/Université Joseph Fourier)

    The Moon meets the planets

    After the Sturgeon Moon has risen and set, the coming evenings offer a good chance to see the now-waning Moon meet the planets of the Solar System in the night sky.

    This is because the Moon tracks eastwards in the sky, night after night, so if there are multiple planets visible in the sky, the Moon often makes an apparent close approach to each one in turn.

    Effectively, the Moon will join in the August 2025 planet parade.

    It begins on 11–13 August when the Moon is close to Saturn, first to the right of the planet, and then to the left of the planet the following evening.

    On the evenings of 15–17 August, the Moon tracks past the beautiful blue open star cluster known as the Pleiades in the constellation Taurus.

    Chart showing the location of Uranus near the Pleiades in August 2025. Credit: Pete Lawrence
    Chart showing the location of Uranus near the Pleiades in August 2025. Credit: Pete Lawrence

    The planet Uranus is currently close to the Pleides, which means the Moon is also passing Uranus, too.

    Get out your binoculars or telescope and see if you can observe the distant world. For more info, read our guide to observing Uranus in August 2025.

    In the very early hours of 18 August, and the following morning of 19 August, if you can get a clear view of the eastern horizon before sunrise, you’ll see the Moon forming a line with Mercury, Venus and Jupiter, stretching upwards.

    Mercury will be very close to the horizon, followed by Venus, then Jupiter and the Moon at the top.

    See Mercury, Venus, Jupiter and the Moon in a straight line in the east on the morning of 18 August 2025. Uranus is also visible, but trickier to see, while Saturn and Neptune are visible in the south. Credit: Stellarium
    See Mercury, Venus, Jupiter and the Moon in a straight line in the east on the morning of 18 August 2025. Uranus is also visible, but trickier to see, while Saturn and Neptune are visible in the south. Credit: Stellarium

    On 20 August, the Moon will have tracked further east, disrupting this multi-planet and Moon alignment in the sky.

    But instead, the Moon forms a beautiful triangle with Venus and Jupiter.

    The Moon forms a triangle with Venus and Jupiter on the morning of 20 August 2025. Credit: Pete Lawrence
    The Moon forms a triangle with Venus and Jupiter on the morning of 20 August 2025. Credit: Pete Lawrence

    Then on 21 August, the Moon is just above Mercury in the very early hours before sunrise.

    From this point onwards, Mercury is becoming much easier to see in the morning sky, having emerged from the glare of the rising Sun.

    This makes the 21 August meeting between Mercury and the Moon a standout moment for observing Mercury.

    The Moon meets Mercury in the very early hours of 21 August. Credit: Pete Lawrence
    The Moon meets Mercury in the very early hours of 21 August. Credit: Pete Lawrence

    From 22 August onwards, the Moon is approaching its ‘new Moon’ phases, meaning it’s beginning to be swallowed by the morning sunrise.

    If you observe the Sturgeon Moon or the Moon’s meeting with the planets this month, share your observations and images with us by emailing contactus@skyatnightmagazine.com

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  • Add-On Lobeglitazone Boosts Glycemic Control in T2D

    Add-On Lobeglitazone Boosts Glycemic Control in T2D

    TOPLINE:

    Patients with type 2 diabetes (T2D) who responded inadequately to sitagliptin plus metformin experienced improvements in glycemic control and insulin sensitivity after lobeglitazone was added to their regimen.

    METHODOLOGY:

    • Metformin and DPP-4 inhibitors such as sitagliptin are widely used for glycemic control in patients with T2D; however, the choice of which agent to add when these therapies fail to achieve target blood glucose levels remains unclear.
    • Researchers in Korea conducted a phase 3 trial from April 2018 to December 2021 to evaluate the efficacy and safety of adding lobeglitazone to the dual therapy regimen of metformin (≥ 1000 mg/d) and sitagliptin (100 mg/d).
    • The study included 231 patients with T2D (mean age, 58.65 years; 56.52% men) whose A1c ranged from 7.0% to 10.0% despite receiving the dual therapy.
    • After a 2-week run-in period, patients were randomly assigned to receive either a 0.5 mg/d dose of lobeglitazone (n = 116) or placebo (n = 115) alongside metformin and sitagliptin for 24 weeks, followed by a 28-week open-label phase in which all patients received lobeglitazone.
    • The primary endpoint was the change from baseline in mean A1c at 24 weeks. Secondary endpoints included changes in additional glycemic and lipid parameters and safety outcomes.

    TAKEAWAY:

    • At week 24, mean A1c levels were 1.03% lower in patients who received lobeglitazone vs placebo (95% CI, -1.23% to -0.82%), with the reduction being maintained until 52 weeks; those who switched from placebo to lobeglitazone at week 24 also saw a reduction in A1c levels by week 52.
    • Additionally, at week 24, a higher proportion of patients receiving lobeglitazone vs placebo achieved A1c levels < 6.5% (27.14% vs 0.87%) and < 7% (53.04% vs 13.04%; both P < .0001).
    • The addition of lobeglitazone to dual therapy significantly improved insulin sensitivity markers compared with placebo at week 24, with effects sustained till week 52; additionally, administration of lobeglitazone reduced low-density lipoprotein cholesterol levels.
    • The incidence of adverse events was not significantly different between the two groups; the incidence of edema and weight gain in some patients receiving lobeglitazone aligned with the known effects of thiazolidinediones.

    IN PRACTICE:

    “The observed improvements in various glucose-related metabolic factors and lipid metabolism indicators with lobeglitazone coadministration may provide valuable evidence for long-term blood glucose management and cardiovascular risk reduction,” the authors of the study wrote.

    SOURCE:

    This study was led by Eun-Gyoung Hong, MD, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, South Korea. It was published online in Diabetes, Obesity and Metabolism.

    LIMITATIONS:

    A longer follow-up might be needed to fully evaluate the sustained effects of the study outcomes and potential side effects.

    DISCLOSURES:

    This study received funding from Chong Kun Dang Pharmaceutical Company. The authors declared having no conflicts of interest.

    This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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  • Prince William is granted permission for homeless youth housing

    Prince William is granted permission for homeless youth housing

    Ruby Gregory

    Local Democracy Reporting Service

    Getty Images A balding man in a blue suit is sat on a sofa. He has a straight face and is clasping his hands together in front of himself. He is mostly bald with very short brown hair on either side. Getty Images

    Prince William launched the Homewards programme in 2023 to demonstrate it is possible to end homelessness

    Land in south London owned by Prince William will be turned into new homes for young people who have experienced homelessness.

    The Duchy of Cornwall owns 60 Sancroft Street in Vauxhall, which be renovated into 16 affordable rentals for 18-25 year olds, according to the Local Democracy Reporting Service.

    In a meeting on 29 July, Lambeth Council unanimously approved the plan which form part of the Prince and Princess of Wales’ Homewards programme which aims to prevent homelessness.

    The first homes will be delivered by the end of 2026 and will be managed by charity Centrepoint.

    The flats will be allocated to people aged 18 to 25 who have been homeless, are at risk of homelessness, or are in supported housing and are ready to live independently.

    Rents will be set at one-third of a tenant’s gross earnings, with 12 of the 16 tenants required to be in full-time employment.

    The remaining four will be supported to find jobs by youth homelessness charity Centrepoint, who will manage the site, and the council.

    Michelle Donovan, head of independent living at Centrepoint, said the scheme will “allow [young people] to hold down a job, end their reliance upon benefits, and escape from homelessness for good.”

    Google A large five-storey building, made of light sand coloured bricks. On the pavement, there is a black lamppost, a parking sign, and two black wheelie bins on the far right. Google

    The building in Lambeth will be converted into 16 affordable flats

    The Duchy is a private estate that funds both the charitable and private activities of the Duke of Cornwall.

    The site was originally built in 1937, and had been used a children’s hospital until 1990 and as accommodation for medical staff until last year.

    The Duchy’s plans also include a former health centre at 65 Sancroft Street, which will be demolished and replaced by a building of 23 flats.

    The majority of these flats will be privately rented, with two allocated as affordable housing at a discounted market rent.

    Vauxhall councillor Martin Bailey said: “This scheme embodies the very best of what planning should achieve, combining a sensitive approach to heritage, outstanding design-quality, and most importantly delivering essential social value in our borough.”

    Lambeth Council A computer-generated image of a large red-brick building, viewed side-on from the front. The main structure has four storeys, with windows arranged in rows on each level. Lambeth Council

    A separate address owned by the Duchy of Cornwall on Sancroft Street will be turned into 23 flats

    The Royal Foundation’s Homewards programme, aims to end homelessness with a five-year campaign launched in 2023.

    Its Innovative Housing Projects span six locations across the UK, including this plan in Lambeth.

    Similar plans were announced last February in Cornwall.

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  • Heatwaves drive spikes in demand for air conditioning across Europe

    Heatwaves drive spikes in demand for air conditioning across Europe

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  • Oil slips as OPEC+ proceeds with September output hike – Reuters

    1. Oil slips as OPEC+ proceeds with September output hike  Reuters
    2. Eight OPEC+ countries raise production by 547,000 bpd  The Express Tribune
    3. V8 nations aim to boost oil output by 0.5m barrels  Dawn
    4. Oil falls $2 a barrel on worries about OPEC+ supply, US jobs data  Dunya News
    5. OPEC+ Confirms Bumper Oil Output Boost  Bloomberg.com

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  • Pakistan ‘Outguns’ India In Fighter Jet Acquisition; Can It Eclipse Indian Military In A Full Scale Clash? OPED

    Pakistan ‘Outguns’ India In Fighter Jet Acquisition; Can It Eclipse Indian Military In A Full Scale Clash? OPED



    India is a land of contradictions. According to the Global Firepower Index 2025, India has the world’s fourth most powerful Air Force after the US, Russia, and China, maintaining a formidable fleet of 2,229 aircraft, including over 500 fighter jets.

    Despite these impressive numbers, India also has the unenviable position of having one of the highest aircraft accident rates during peacetime in Asia.

    The Indian Air Force (IAF) has lost five aircraft so far in 2025 in peacetime operations: three Jaguars, one Mirage-2000, and one Antonov An-32. IAF also lost some jets during the brief four-day war with Pakistan in May.

    In fact, Pakistan, India’s archenemy, whose Air Force is ranked seventh on the Global Firepower Index, claims that it has consistently outperformed the IAF during the last three clashes.

    While Pakistani claims must be taken not just with a pinch of salt but a handful of salt, it can’t be denied that Islamabad has scored a point or two over the IAF in the recent clashes.

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    Indeed, notwithstanding its much smaller and debt-ridden economy and persistent political instability, Pakistan has been ‘consistently’ defeating its much larger, more prosperous, and stable neighbour in fighter jet acquisitions.

    However, high aircraft losses during peacetime operations and a woefully slow defense acquisition process are not the only maladies afflicting the IAF. Another persistent issue, at least since the last three decades, has been the IAF’s small but highly publicized losses during such operations as Kargil (1999), Balakot (2019), and Operation Sindoor (2025).

    But before we turn our attention to combat losses, first, let us unravel the IAF’s unbelievably high peacetime losses and slow defense acquisition policy compared with Pakistan’s swift fighter jet acquisitions.

    IAF’s High Peacetime Losses

    The IAF lost eight aircraft in 2024, another eight in 2023, five in 2022, 11 in 2021, and five in 2020, all of them during routine peacetime missions. Since 2020, India has lost 42 aircraft, losing more than seven aircraft every year.

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    Between 2015 and 2024, India lost a total of 104 aircraft, or nearly six squadrons.

    The IAF currently has a fighter squadron strength of 29, as against the sanctioned strength of 42. The IAF is short of 11 fighter squadrons.

    However, India has lost aircraft equivalent to 14 squadrons (255 aircraft) during the last two decades. Apart from the expensive aircraft, the IAF has also lost priceless pilots during these crashes.

    Between 2012 and 2021, India lost 73 IAF pilots in various crashes, averaging more than seven pilots every year. The figures for previous decades are even more shocking.

    For instance, India lost 122 IAF pilots between 2002 and 2011, and a further 190 IAF pilots between 1992 and 2001.

    In the decade before that (1982-1991), India lost a staggering 230 pilots, the highest figure in any decade since independence (not counting the decade between 1962-1971, when India fought three wars – 1962, 1965, and 1971 – and lost 333 IAF pilots).

    According to a study by defense analyst Colonel Ajai Shukla (Retd.), between 1952 and 2021, India lost 1,305 pilots over the seven decades, an overwhelming majority of whom died during non-combat missions.

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    According to Bharat Rakshak, a privately run digital platform that has meticulously compiled data on all IAF losses between 1948 and 2025, the IAF has lost a total of 1,804 aircraft (excluding helicopters), with the vast majority of these losses occurring during non-combat missions.

    According to one analysis, of the 1,804 aircraft lost, only about 143 aircraft were lost during combat missions. This means that the IAF has lost only one in 12 aircraft during combat missions, and the remaining 11 during peacetime missions.

    These numbers should shock any Air Force in the world. They’re even more shocking for a country that is the world’s fourth-largest economy and boasts of the world’s fourth most powerful air force.

    Two Decades & Still Waiting: India’s MRFA Deal

    To understand everything that is wrong with India’s slow defense acquisition policy, one should only look at India’s MRFA (Medium Role Fighter Aircraft) deal fiasco. First envisioned in 2001, the agreement has yet to be signed as of 2025.

    The IAF first floated the Medium Multi-Role Combat Aircraft (MMRCA) tender to procure 126 new warplanes from foreign vendors in 2007. The move came after the Light Combat Aircraft (LCA) Tejas, a planned indigenous replacement for the IAF’s aging fleet of Soviet-era MiG-21s, faced delays in development.

    The contest initially featured six fighter aircraft: Boeing F/A-18E/F Super Hornet, Dassault Rafale, Eurofighter Typhoon, Lockheed Martin F-16, Mikoyan MiG-35, and Saab Gripen. By 2012, the Eurofighter Typhoon and Dassault Rafale emerged as final contenders, with Rafale winning the competition.

    However, the deal stalled due to disagreements over production in India. India officially withdrew the 126-aircraft MMRCA tender in July 2015. Instead, in 2016, Prime Minister Narendra Modi, during his visit to France, announced that India would purchase 36 Rafales in fly-away condition.

    To many, it looked like the end of India’s MMRCA deal. However, in 2018, MMRCA was reincarnated as Multi Role Fighter Aircraft (MRFA) deal when the government issued a Request for Information (RFI) for the procurement of 114 fighter jets.

    This tender is loosely termed as ‘MMRCA 2.0’. The new fighters are expected to replace the aging MiG-21s, Mirage 2000s, and Jaguars. In April 2019, it was announced that the estimated acquisition cost of the warplanes is US$18 billion.

    In 2025, nearly 24 years after the deal was first envisioned, India has yet to issue the new tender for the contract.

    India’s Tejas Program: Four Decades In-The-Making

    Not just the foreign fighter jet acquisition program, even India’s indigenous fighter jet development project is suffering from similar delays. The LCA Tejas project was first envisaged in the 1980s.

    Four decades later, India has been able to induct just 38 LCA Tejas Mk-1 fighter jets. The planned induction of upgraded Tejas Mk-1A, initially scheduled for March 2024, is running behind schedule.

    This delay has put the IAF in a vulnerable position, where it is operating just 31 fighter jet squadrons, as against the sanctioned strength of 42 fighter jet squadrons. After IAF retires the last two squadrons of MiG-21 Bisons in September, the IAF strength will further come down to just 29 squadrons.

    The Indian Air Force Tejas performs at the opening ceremony of the Singapore Air Show on February 15, 2022.

    The combination of HAL’s inability to deliver on time, coupled with inordinate delays in the MRFA tender, means that the IAF is operating with its lowest strength since 1965.

    PAF Beating India In Fighter Jet Acquisitions

    Ironically, despite being a larger economy, it is Pakistan that has consistently beaten India in acquiring the latest fighter jets for the last seven decades.

    Commenting on Pakistan’s competitive edge in terms of air power, former IAF Air Marshal Anil Chopra writes: “For a long time, military-controlled Pakistan has looked ahead and taken preemptive decisions. Starting in 1954, the Pakistan Air Force (PAF) acquired 102 much superior U.S.-built F-86F ‘Sabre.’ Around the same time, India got the Dassault Ouragans (Toofani). The Indian Air Force (IAF) acquired the Dassault Mystère IV a few years later.”

    “In 1961, Pakistan, as a major non-NATO ally, received F-104 Starfighters from the USA under the Mutual Assistance Program. The IAF responded by purchasing the Soviet MiG-21, which entered service in 1964.”

    Similarly, in 1981, the USA cleared F-16 sales to Pakistan as part of an aid package. India signed for Mirage 2000 in 1982.

    PAF inducted the first JF-17 squadron in February 2010, vis-à-vis IAF inducting LCA Mk1 in January 2015. PAF already has close to 150 of these homegrown fighters. India has built around 38 LCA.

    Furthermore, Chopra writes, the first batch of JF-17C Block 3 aircraft was inducted into the PAF in March 2023. India’s LCA Mk1A will be inducted soon. India signed up for the Rafale in 2016, and Pakistan responded with the purchase of J-10CE, signing the deal in 2021.

    Pakistan might maintain a competitive edge over India even in fifth-generation fighter jets. According to reports, it has ordered 40 Chinese J-35A stealth fighter jets, and is expected to receive its first deliveries in early 2026.

    On the contrary, India’s indigenous AMCA program is at least a decade away, and it has not yet signed a deal for acquiring a foreign fifth-generation fighter jet.

    Experts believe that India’s institution-based democratic setup might be hurting its defense acquisition process, as any deal has to pass scrutiny of many independent bodies, often at loggerheads with each other. Whereas in Pakistan, the Army reigns supreme and can steamroll any opposition to fat defense deals.

    From Kargil To Op Sindoor

    Much has been written about the IAF’s combat losses during Op Sindoor. Pakistan claims it shot down six Indian fighter jets, including three Rafales. The IAF has acknowledged combat losses but has not provided any details on the make or number of aircraft lost.

    However, the IAF has also suffered combat losses in two more recent clashes with Pakistan.

    In 2019, India lost a MiG-21 Bison in an aerial clash with the PAF, and its fighter pilot Abhinandan Varthaman was captured by Pakistan. The IAF claimed that Wing Commander Abhinandan Varthaman was able to shoot down a Pakistani F-16 before losing his own aircraft; however, Pakistan denied these claims.

    An Indian Air Force (IAF) MIG-21 passes near Sukhoi-30 fighter jets before a drill for Air Force Day celebrations in Kalikunda IAF airbase around 170 km west of Kolkata on September 29, 2011. Indian Air Force Day is celebrated on October 8 each year. AFP PHOTO/ Dibyangshu SARKAR (Photo by DIBYANGSHU SARKAR / AFP)

    Earlier in Kargil (1999), the IAF lost three aircraft as part of Operation Safed Sagar, which supported the Indian Army in flushing out Pakistani intruders from the Kargil sector. The losses occurred in the initial phase of air operations, between May 27 and 28, 1999, due to enemy surface-to-air missiles (SAMs) and ground fire in the high-altitude, rugged terrain.

    On May 27, a MiG-27 flown by Flt Lt Nachiketa, from No. 9 Squadron, was on a strike mission in the Batalik sector. The aircraft suffered an engine flameout, likely due to mechanical failure exacerbated by the high-altitude conditions. Nachiketa was captured by Pakistani forces and became a prisoner of war (POW). He was repatriated on June 3, 1999, after eight days in captivity.

    On the same day, Sqn Ldr Ajay Ahuja, flying a MiG-21M from No. 17 Squadron, was tasked with locating the downed MiG-27 pilot (Nachiketa). While conducting a search over enemy positions in the Batalik sector, his aircraft was hit by a Pakistani shoulder-fired FIM-92 Stinger missile. Ahuja was captured and killed by Pakistani troops or irregulars on the ground.

    The IAF also lost a Mi-17 Helicopter the next day.

    The Kargil (1999), Balakot (2019), and Op Sindoor (2025) were entirely different missions, fought under very different circumstances, and no generalizations could be made between the three. However, it remains a fact that the IAF suffered combat losses in all three missions despite winning the bigger battle.

    The Counter Point: Combat Losses Never Define Victory Or Defeat

    However, despite the combat losses suffered by the IAF, an argument could be made that, historically, victory or defeat has never been defined by counting combat losses.

    In the recent US operations against the Houthis militia, the U.S. Navy lost three F/A-18E Super Hornet fighter jets. However, no one is making an argument that the US mission failed simply because the US lost three fighter jets.

    Senior award-winning Indian journalist Prakash Nanda writes: “Records from the now-defunct U.S. Army Air Forces indicate that at least 100,000 planes were destroyed during World War II. The U.S. is said to have lost 65,164 airplanes in combat, training accidents, and other incidents between December 1941 and August 1945 while destroying 40,259 enemy aircraft during the war.”

    In other words, in World War II, Americans lost more planes than they destroyed of the enemy. But ultimately, it is they who won, not America’s enemies, Nanda argued in an article for the EurAsian Times earlier.

    Similarly, Nanda argued that during the 1991 Gulf War, the U.S. lost 28 fixed-wing aircraft in combat and 12 in non-combat situations. Additionally, 23 U.S. helicopters were lost, with 5 in combat and 18 in non-combat situations. In total, the US was reported to have lost 75 aircraft, with 63 U.S. aircraft and 12 allied aircraft.

    During the 1999 air campaign over Serbia, the US and NATO forces lost two fighter planes. One was a USAF F-16C fighter jet, and the other was a cutting-edge F-117 Nighthawk stealth attack aircraft. Both were shot down by the Serbian air defense systems.

    But does anyone argue that the US lost these wars?

    Ultimately, victory or defeat is defined not by combat losses but by who achieved their war goals.

    Seen from this perspective, one can argue that despite its combat losses, the IAF did deliver results in all three missions.

    In Kargil, the IAF bombed heavily defended enemy positions, and ultimately, India was able to free the Kargil heights from Pakistani intruders.

    In Balakot, the IAF was able to penetrate deep inside Pakistan, despite the PAF being on high alert. And in Op Sindoor, India was able to bomb nine terror camps deep inside Pakistan in precision air strikes.

    The PAF was on high alert and was anticipating an attack, but it still failed to stop the IAF precision strikes. Again, on May 10, the IAF attacked as many as 11 frontline Pakistani air bases in precision strikes.

    So, irrespective of who lost how many jets, it is undeniable that the IAF fulfilled its mission tasks.

    Regarding Pakistan beating India in ordering a fifth-generation aircraft, Islamabad might have gotten off-the-shelf Chinese jets; however, India is making significant strides in developing indigenous defense platforms.

    The LCA Tejas, except for its GE-sourced engine, is an entirely Indian project. Furthermore, India has made significant progress in developing domestic radars and aircraft munitions, such as BrahMos and Astra. Slowly, but steadily, India is progressing towards ‘self-reliance’ in defense.

    The outsized influence of the Pakistani Army might make it easier for Islamabad to strike defense deals; however, the same army has also pushed Pakistan into political instability multiple times.

    Pakistan, despite its vastly important geo-strategic position, is a debt-ridden country, totally dependent on China for its survival.

    Lastly, the PAF’s competitive edge over the IAF in terms of advanced fighter jets has not translated into a single victory for Islamabad over New Delhi in the last seven decades.

    On the other hand, the IAF, despite its slow acquisition process, horrible accident rate during peacetime, and combat setbacks, has delivered results whenever a task was given to it.

    • Sumit Ahlawat has over a decade of experience in news media. He has worked with Press Trust of India, Times Now, Zee News, Economic Times, and Microsoft News. He holds a Master’s Degree in International Media and Modern History from the University of Sheffield, UK. 
    • THIS IS AN OPINION ARTICLE. VIEWS PERSONAL OF THE AUTHOR. 
    • He can be reached at ahlawat.sumit85 (at) gmail.com

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  • The expression and prognostic value of ALDOA in breast cancer

    The expression and prognostic value of ALDOA in breast cancer

    Introduction

    The most prevalent malignancy among women is breast cancer (BC).1 Metabolic reprogramming and immune evasion are two main features of the malignant transformation of BC, which facilitate cancer cell proliferation.2 The accumulation of reactive oxygen species (ROS) and oxidative stress are associated with many risk factors, including age, genetic susceptibility, exposure to ionizing radiation, and estrogen metabolism.3

    Aldolase A (ALDOA) is a crucial enzyme within the glycolytic pathway. The process enables the reversible conversion of fructose-1,6-bisphosphate into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Vertebrates possess three aldolase isozymes, ALDOA, ALDOB, and ALDOC, characterized by distinct electrophoretic and catalytic properties. ALDOA represents the primary aldolase isozyme in tumor tissues, and the systemic increase in aldolase activity due to ALDOA upregulation in these tissues is a distinctive characteristic of cancer.4,5 ALDOA has been observed to be overexpressed in a variety of malignant tumors, including gastric cancer,6 hepatocellular carcinoma,7 colorectal cancer,8 cervical cancer,9 kidney cancer10 and triple-negative BC.11,12 Numerous studies indicate that ALDOA may be an independent prognostic factor.13–15 Chang et al reported ALDOA was overexpressed in breast cancer tissues and a correlation between ALDOA expression levels and overall survival.16 However, the potential correlation between ALDOA expression and clinicopathological features remains elusive and needs further evaluation.

    To ascertain the clinical implications of ALDOA in BC, this study examined any potential correlation between its expression and clinicopathological traits. Furthermore, we assessed the predictive significance of ALDOA in BC using the Kaplan-Meier plotter.

    Methods

    ALDOA Expression Analysis

    The mRNA expression of ALDOA in pan-cancer data was analyzed by using the Tumor Immune Estimate Resource (TIMER) database (https://cistrome.shinyapps.io/timer/). The data of ALDOA expression in BC tissue and in normal tissue was analyzed using the Gene Expressing Profiling Interactive Analysis (GEPIA; http://gepia.cancer-pku.cn/) platform, the UALCAN web portal (http://ualcan.path.uab.edu/), and the BC Gene-expression miner (bc-GenExminer) v5.1 (http://bcgenex.ico.unicancer.fr).

    Correlation Analysis of ALDOA and Clinicopathological Features

    The Gene Expressing Profiling Interactive Analysis (GEPIA; http://gepia.cancer-pku.cn/) platform, the UALCAN web portal (http://ualcan.path.uab.edu/), and the BC Gene-expression miner (bc-GenExminer) v5.1 (http://bcgenex.ico.unicancer.fr) were used to analyze the correlation of ALDOA and clinicopathological features of BC patients. We used these databases based on the Pearson χ2 test to analyze ALDOA mRNA expression among tumor and normal samples and P values < 0.05 to evaluate the statistical significance. The user-friendly web portal bc-GenExminer v5.1 includes BC patients’ clinicopathological data based on microarray and RNA-seq (Jézéquel et al, 2012). The expression of GSTMs according to Scarff-Bloom-Richardson (SBR) grade and intrinsic molecular subtypes was identified by the Prediction Analysis of Microarray 50 (PAM50) test. The significant P value (P < 0.05) was determined using Dunnett-Tukey-Kramer test and Welch’s t-test.

    Survival Analysis

    The association between ALDOA mRNA expression and BC patient survival, including overall survival (OS), recurrence-free survival (RFS) and distance metastasis-free survival (DMFS), was evaluated while using the Kaplan-Meier (K-M) Plotter (https://kmplot.com) database. P < 0.05 were considered as significant.

    Human BC Tissues

    The Department of General Surgery at Soochow University’s First Affiliated Hospital collected 96 BC and 50 adjacent healthy samples from BC patients with histological diagnoses who had radical surgery. None of the participants had chemotherapy or radiotherapy before surgery. The ethics board of the relevant institution approved this study (IRB number is 2022-083), which was conducted in compliance with the Declaration of Helsinki. Written informed consent was obtained from all patients prior to study commencement.

    Immunohistochemistry (IHC)

    Following defined procedures, the paraffin-embedded tissues were sectioned to a thickness of 5 μm, incubated at 4°C overnight with a monoclonal human ALDOA antibody (dilution 1:100; #11305-1-AP, Proteintech), stained using a staining kit (Zhongshan Biotechnology, Bei-jing, China), followed by visualization. After this, the staining score was evaluated based on positive cell rate and color intensity.17,18 The staining was divided by color intensity into not colored, light yellow, brown, and tan and is recorded as 0, 1, 2, and 3, respectively. Positive cell rate of <25% was a score of 1, positive cell rate of 25–50% was a score of 2, positive cell rate of 51–75% was a score of 3, positive cell rate of >75% was a score of 4. The final score was calculated by the multiple of the intensity and extent score. A final score of 0 was considered as −; 1–4 as +; 5–8 as ++; 9–12 as +++. In our study, ++ or +++ was considered as high expression, and – or + as no or low expression.

    Statistical Analysis

    The statistical significance was assessed by one-way analysis of variance or Student’s t-test (paired, unpaired, or two-tailed). The difference in mRNA expression between groups was made by Welch’s and Dunnett-Turkey-Kramer’s tests. The associations between ALDOA expression and clinicopathologic variables were examined using the Pearson χ2 test. K-M analysis was used for survival analysis. It was determined that P < 0.05 was statistically significant.

    Results

    ALDOA Expression Levels are Higher in BC Tumor Tissues Compared to Normal Tissues

    The RNA-seq data analysis from the TIMER database shows that most cancer tissues had ALDOA expression higher than in normal tissues, including 13 malignancies like BC (Figure 1A). According to the UALCAN database and the bc-GenExMiner v5.1 cohort, BC tissues had a considerably higher amount of ALDOA than normal tissues (Figure 1B and C, P < 0.001). ALDOA expression was higher in BC tumors than in normal breast tissues in the GEPIA dataset (Figure 1D; insignificant but marginal).

    Figure 1 ALDOA expression in human BC tissues. (A) ALDOA expression in tumor and normal tissues in TIMER database. (B–D) ALDOA expression in BC tumor and normal tissues in bc‐GenExMiner v5.1 (B), UALCAN (C) and GEPIA (D) databases. (E) Representative IHC staining of ALDOA in human BC tissues and normal tissues. (F) Analysis of ALDOA IHC scores in human BC tissues and normal tissues. ***P < 0.001.

    Furthermore, IHC was used to assess the expression of the ALDOA protein in BC tissues and normal breast tissues. In BC tissue, ALDOA protein-positive staining increased (Figure 1E). Importantly, human BC tissues had higher IHC scores than normal tissues (Figure 1F; P < 0.001).

    Relationship Between ALDOA Expression and BC Patients’ Clinicopathological Features

    This study used the bc-GenExMiner v5.1 (Table 1) and UALCAN (Table 2) databases to examine the relationship between ALDOA expression and clinicopathological variables. Higher expression of ALDOA was linked to micropapillary BC, lymph node metastasis (LNM), older age, and high Ki67 expression. However, the correlations between ALDOA expressions with the staging of LNM patient’s gender and TNM stage were not significant (Figure 2).

    Table 1 The Correlation Between ALDOA Expression and Clinicopathological Features of BC Patients Using the bc‐GenExMiner v5.1 Database

    Table 2 The Correlation Between ALDOA Expression and Clinicopathological Features of BC Patients Using the UALCAN Database

    Figure 2 ALDOA expression in different subgroups of human BC tumor tissues in bc‐GenExMiner v5.1 and UALCAN databases. (A) ALDOA expression in BC tumors of different histological types in bc‐GenExMiner v5.1 database. (B and C) ALDOA expression in BC tumors with or without LNM in bc‐GenExMiner v5.1 (B) and UALCAN (C) databases. (D and E) ALDOA expression in BC tumors based on patient’s age in bc‐GenExMiner v5.1 (D) and UALCAN (E) databases. (F) ALDOA expression in BC tumors based on patient’s gender in UALCAN database. (G) ALDOA expression in BC tumors based on ki-67 status in bc‐GenExMiner v5.1 database. (H and I) ALDOA expression in BC tumors based on tumor stages in bc‐GenExMiner v5.1 (H) and UALCAN (I) databases. ***P < 0.001.

    Abbreviation: ns, nonsignificant.

    Afterward, this study examined the correlation between ALDOA expression and the pathological factors of BC. In the bc‐GenExMiner v5.1 database, elevated expression of ALDOA was associated with ER+ (Figure 3A), PR+ (Figure 3B), and ER+/PR+ (Figure 3C). However, the correlations between ALDOA expression and HER2 status were insignificant (Figure 3D). ALDOA expression in BC tumors based on PAM50 molecular subtypes was also investigated, and results showed that non-basal-like (including HER2-enriched (HER2-E), Luminal A and Luminal B subgroups) BC possessed higher ALDOA expression than the basal-like subtype (Figure 3E and F). The ALDOA expression of non-triple negative breast cancer (TNBC) tissue was higher than that of TNBC (including LAR, MLIA, BLIA, and BLIS subgroups) tissue (P = 0.0043, Figure 3G and H). Among different subtypes of TNBC, the luminal androgen receptor (LAR) subgroup showed higher ALDOA expression than other subtypes (P < 0.0001, Figure 3H and I).

    Figure 3 ALDOA expression in different subgroups of human BC tumor tissues in bc‐GenExMiner v5.1 database. (A–D) ALDOA expression in BC tumors based on ER (A), PR (B), ER/PR (C) and HER2 (D) status. (E) ALDOA expression in BC tumors based on PAM50 molecular subtypes. (F and G) ALDOA expression in BC tumors based on basal-like (PAM50 (F)) and TNBC (G) and status. (H and I) ALDOA expression in BC tumors based on non-TNBC and TNBC subtypes.

    In the bc‐GenExMiner v5.1 database, the correlations between ALDOA expression in BC tumors with breast cancer susceptibility gene (BRCA) 1 (Figure 4A, P = 0.9913), BRCA2 (Figure 4B, P = 0.3623) or BRCA1/2 status (Figure 4C, P = 0.3494) were not significant. The GES analysis from bc-GenExMiner database revealed that the ALDOA expression level of p53 wild-type BC was higher than p53 mutated (Figure 4D, P = 0.0002). However, in the IHC analysis from bc-GenExMiner database and the UALCAN database, the status of P53 was not related to the ALDOA expression in BC (Figure 4E and F). Moreover, higher ALDOA levels were substantially correlated with higher Scarff-Bloom-Richardson (SBR) grade (Figure 4G, P = 0.002) and Nottingham Prognostic Index (NPI) (Figure 4H, P = 0.0004). Asian patients showed the highest ALDOA expression among all three races (Figure 4I, P < 0.001).

    Figure 4 ALDOA expression in different subgroups of human BC tumor tissues in bc‐GenExMiner v5.1 and UALCAN databases. (A–C) ALDOA expression in BC tumors based on BRCA1 (A), BRCA2 (B) AND BRCA1/2 status in bc‐GenExMiner v5.1 database. (D and E) ALDOA expression in BC tumors based on p53 (GES (D)), p53 (IHC (E)) status in bc‐GenExMiner v5.1 database. (F) ALDOA expression in BC tumors based on p53 status in UALCAN database. (G and H) ALDOA expression in BC tumors based on Scarff-Bloom-Richardson (SBR (G)) grade and NPI (Nottingham prognostic index (H)) status in bc‐GenExMiner v5.1 database. (I) ALDOA expression in BC tumors based on patient’s race in UALCAN database. ***P < 0.001.

    Abbreviation: ns, nonsignificant.

    Moreover, the relationship between ALDOA expression and the clinical characteristics in 96 BC patients who underwent radical surgery was investigated using IHC (Table 3). Increased ALODA expression was shown to be significantly associated with higher histological grade (Table 3, P < 0.001) and lymph node metastasis (Table 3, P = 0.043). However, no significant correlation was found between ALDOA expression and TNM stage, vascular invasion, tumor location, tumor size, or age (Table 3, P > 0.05).

    Table 3 The Relationships Between ALDOA and Clinicopathological Factors in 96 Patients with Breast Cancer

    The OS of BC Patients is Correlated with ALDOA Expression in Various Subgroups

    The correlation between ALDOA mRNA expression in various subgroups and OS of BC patients was determined using the K-M survival curve analysis from the K-M Plotter database. In BC patients, shorter OS was predicted by higher ALDOA expression (Figure 5A, HR = 1.34, P = 0.0027). The results of the subgroup analysis showed that in the ER-positive (Figure 5B, HR = 1.42, P = 0.003), ER-negative (Figure 5C, HR = 1.6, P = 0.0067), PR-positive (Figure 5D, HR = 2.89, P = 0.006), and HER2-positive (Figure 5F, HR = 1.57, P = 0.014) subgroups, a shorter OS rate was associated with higher ALDOA expression. ALDOA expression did not, however, significantly correlate with the OS of BC patients who were PR negative (Figure 5E, HR = 1.56, P = 0.071) or HER2 negative (Figure 5G, HR = 1.23, P = 0.076). Higher ALDOA level was significantly associated with shorter overall survival in lymph node-negative patients (Figure 5I, HR = 1.58, P = 0.0086), this correlation was not significant in the lymph node-positive cohort (Figure 5H, HR = 1.23, P = 0.23).

    Figure 5 ALDOA expression in different subgroups correlates with overall survival (OS) of patients with BC from Kaplan-Meier plotter database. (A) Kaplan-Meier survival curve analysis shows OS of BC patients. (B and C) Kaplan-Meier survival curve analysis shows OS of BC patients based on ER status ((B) ER positive; (C) ER negative). (D and E) Kaplan-Meier survival curve analysis shows OS of BC patients based on PR status ((D) PR positive; (E) PR negative). (F and G) Kaplan-Meier survival curve analysis shows OS of BC patients based on HER2 status ((F) HER2 positive; (G) HER2 negative). (H and I) Kaplan-Meier survival curve analysis shows OS of BC patients with LNM (H) or without LNM (I).

    Abbreviation: HR, hazard ratio.

    OS was significantly shortened in high ALDOA expressing basal (Figure 6A, HR = 1.94, P = 0.0011), luminal A (Figure 6B, HR = 1.42, P = 0.033), and luminal B (Figure 6C, HR = 1.56, P = 0.017) BC patients when taking StGallen molecular subtypes into account. However, there was no significant correlation between the OS of BC patients with HER2 and ALDOA expression (Figure 6D, HR = 1.64, P = 0.086). Patients with p53 wild-type tumors exhibiting high ALDOA expression demonstrated significantly shorter overall survival (Figure 6F, HR = 1.95, P = 0.032). This association was not significant in the p53-mutated subgroup (Figure 6E, HR = 2.2, P = 0.094). Furthermore, high ALDOA expression is related to shorter OS in histological grade 1 (Figure 6G, HR = 2.29, P = 0.053, not significant, but marginal) and grade 2 (Figure 6H, HR = 1.67, P = 0.011) subgroups. Still, there was no discernible correlation between the OS of the histological grade 3 subgroup and the expression of ALDOA mRNA (Figure 6I, HR = 1.23, P = 0.26).

    Figure 6 ALDOA expression in different subgroups correlates with OS of patients with BC from Kaplan-Meier plotter database. (A–D) Kaplan-Meier survival curve analysis shows OS of BC patients based on StGallen molecular subtypes ((A) basal; (B) luminal A; (C) luminal B; (D) HER2 positive). (E and F) Kaplan-Meier survival curve analysis shows OS of BC patients based on p53 status ((E) mutated; (F) wild type). (G–I) Kaplan-Meier survival curve analysis shows OS of BC patients based on histological grade ((G) grade 1; (H) grade 2; (I) grade 3).

    The RFS of BC Patients is Correlated with ALDOA Expression in Various Subgroups

    K-M survival curve analysis employing the K-M Plotter database showed that ALDOA mRNA expression was linked to relapse-free survival (RFS) of BC patients in several categories. BC patients with high ALDOA expression generally had significantly shorter RFS than those with low ALDOA expression (Figure 7A, HR = 1.15, P = 0.0085). Considering different pathological subgroups, shortened RFS was related to higher ALDOA expression regardless of the ER and PR status (Figure 7B–E), and also in HER2 positive BC patients (Figure 7F, HR = 1.42, P = 0.0017). However, among HER2-negative patients, there was no significant correlation between ALDOA expression and RFS (Figure 7G, HR = 1.09, P = 0.12). Elevated ALDOA expression corresponded to reduced RFS in LNM negative breast cancer cases (Figure 7I, HR = 1.22, P = 0.018). Conversely, nodal metastasis-positive patients exhibited no statistically association between ALDOA levels and RFS outcomes (Figure 7H, HR = 1.17, P = 0.13). Considering LNM status, shortened RFS was related to higher ALDOA expression in BC patients without LNM (Figure 7I, HR = 1.22, P = 0.018). In contrast, in patients with LNM, the correlation was not significant (Figure 7H, HR = 1.17, P = 0.13).

    Figure 7 ALDOA expression in different subgroups correlates with relapse‐free survival (RFS) of patients with BC from Kaplan-Meier plotter database. (A) Kaplan-Meier survival curve analysis shows RFS of BC patients. (B and C) Kaplan-Meier survival curve analysis shows RFS of BC patients based on ER status ((B) ER positive; (C) ER negative). (D and E) Kaplan-Meier survival curve analysis shows RFS of BC patients based on PR status ((D) PR positive; (E) PR negative). (F and G) Kaplan-Meier survival curve analysis shows RFS of BC patients based on HER2 status ((F) HER2 positive; (G) HER2 negative). (H and I) Kaplan-Meier survival curve analysis shows RFS of BC patients with LNM (H) or without LNM (I).

    Abbreviation: HR, hazard ratio.

    In the luminal A (Figure 8B, HR = 1.28, P = 0.0044), basal (Figure 8A, HR = 1.32, P = 0.014), and luminal B (Figure 8C, HR = 1.21, P = 0.033) cohorts, pronounced RFS reduction is significantly related to high ALDOA expression. In contrast, the association between ALDOA expression and the RFS of HER2-positive BC patients (Figure 8D, HR = 1.39, P = 0.067) was not significant. RFS was remarkably shortened in high ALDOA expressing p53 mutated BC patients (Figure 8E, HR = 3.61, P = 3.1e-05) and in the p53 wild type individuals (Figure 8F, HR = 1.39, P = 0.17), the association was not significant. Considering histological grade status, shortened RFS was related to higher ALDOA expression in BC patients with grade 1 subgroup (Figure 8G, HR = 1.65, P = 0.054, not significant, but marginal). The ALDOA mRNA expression and RFS of the histological grade 2 (Figure 8H, HR = 1.2, P = 0.1) and grade 3 (Figure 8I, HR = 1.19, P = 0.12) subgroups showed no discernible correlation.

    Figure 8 ALDOA expression in different subgroups correlates with RFS of patients with BC from Kaplan-Meier plotter database. (A–D) Kaplan-Meier survival curve analysis shows RFS of BC patients based on StGallen molecular subtypes ((A) basal; (B) luminal A; (C) luminal B; (D) HER2 positive). (E and F) Kaplan-Meier survival curve analysis shows RFS of BC patients based on p53 status ((E) mutated; (F) wild type). (G–I) Kaplan-Meier survival curve analysis shows RFS of BC patients based on histological grade ((G) grade 1; (H) grade 2; (I) grade 3).

    The DMFS of BC Patients is Correlated with ALDOA Expression in Various Subgroups

    We then investigated the connection between ALDOA expression in different subgroups and the DMFS of BC patients using the K-M survival curve analysis from the K-M Plotter database. In general, the association between ALDOA expression and the distant metastasis-free survival (DMFS) of BC patients was insignificant (Figure 9A, HR = 0.93, P = 0.37). Shorter DMFS was linked to increased ALDOA expression in BC patients with both ER-positive (Figure 9B, HR = 1.2, P = 0.066, insignificant, but marginal) and ER-negative (Figure 9C, HR = 1.34, P = 0.039) subgroups. Regardless of PR and HER2 status, there was no discernible correlation between DMFS and ALDOA mRNA expression in BC patients (Figure 9D–G). Unexpected, prolonged DMFS was related to higher ALDOA expression in BC patients with LNM (Figure 9H, HR = 0.72, P = 0.01), while in patients without LNM, the correlation was not significant (Figure 9I, HR = 1.19, P = 0.18).

    Figure 9 ALDOA expression in different subgroups correlates with distance metastasis-free survival (DMFS) of patients with BC from Kaplan-Meier plotter database. (A) Kaplan-Meier survival curve analysis shows DMFS of BC patients. (B and C) Kaplan-Meier survival curve analysis shows DMFS of BC patients based on ER status ((B) ER positive; (C) ER negative). (D and E) Kaplan-Meier survival curve analysis shows DMFS of BC patients based on PR status ((D) PR positive; (E) PR negative). (F and G) Kaplan-Meier survival curve analysis shows DMFS of BC patients based on HER2 status ((F) HER2 positive; (G) HER2 negative). (H and I) Kaplan-Meier survival curve analysis shows DMFS of BC patients with LNM (H) or without LNM (I).

    Abbreviation: HR, hazard ratio.

    Regarding the StGallen molecular subtypes, DMFS was significantly shortened in high ALDOA expressing basal (Figure 10A, HR = 1.64, P = 0.014) and luminal A (Figure 10B, HR = 1.4, P = 0.017) BC patients. The correlation between ALDOA expression and DMFS in the luminal B (Figure 10C, HR = 1.14, P = 0.36) and HER2 positive subgroups (Figure 10D, HR = 0.75, P = 0.32) was not statistically significant. Shortened DMFS was associated with high ALDOA expression in both p53 mutated (Figure 10E, HR = 3.29, P = 0.019) and p53 wild type (Figure 10F, HR = 2.19, P = 0.029) subgroups. Additionally, high ALDOA expression was related to shorter DMFS in histological grade 1 BC patients (Figure 10G, HR = 3.91, P = 0.00039). Still, the ALDOA mRNA expression and DMFS of histological grade 2 (Figure 10H, HR = 0.85, P = 0.28) and grade 3 (Figure 10I, HR = 0.85, P = 0.21) BC patients showed no significant correlation.

    Figure 10 ALDOA expression in different subgroups correlates with DMFS of patients with BC from Kaplan-Meier plotter database. (A–D) Kaplan-Meier survival curve analysis shows DMFS of BC patients based on StGallen molecular subtypes ((A) basal; (B) luminal A; (C) luminal B; (D) HER2 positive). (E and F) Kaplan-Meier survival curve analysis shows DMFS of BC patients based on p53 status ((E) mutated; (F) wild type). (G–I) Kaplan-Meier survival curve analysis shows DMFS of BC patients based on histological grade ((G) grade 1; (H) grade 2; (I) grade 3).

    Discussion

    Despite extensive research on molecular targeted drugs, chemotherapy and hormone therapy are still the first line of BC treatment.1 However, an improved comprehension of the mechanisms by which malignant cells evade the immune system and the advancement of specific immune checkpoint antagonists has introduced novel therapeutic options.19 It is necessary to identify new molecular targets. This study offers insight into ALDOA’s potential function as a BC biomarker.

    Initially, data from internet datasets were analyzed to compare ALDOA expression. ALDOA mRNA levels were observed to be elevated in breast tumors relative to normal and tumor-adjacent tissues, corroborating prior studies that demonstrated a significant increase in ALDOA transcript expression across all breast tumor subtypes compared to normal tissues, suggesting that ALDOA may represent a novel oncogene.12 The above conclusion was verified by IHC. Comparative analysis of various breast cancer subtypes revealed elevated ALDOA expression in specific subtypes, including micropapillary, luminal B, non-basal-like, non-TNBC, and LAR, influencing therapeutic strategies and prognostic outcomes.

    Following this, the bc-GenExMiner v5.1 and UALCAN databases were employed to systematically analyze the correlation between ALDOA expression and several clinicopathological variables. Overexpression of ALDOA was linked to LNM, older age, and high Ki67 expression. There was no statistical significance in gender, cancer stage, or HER2 status in the analysis. Notably, although ALDOA expression was correlated with LNM, the stage of LNM did not affect it. Aside from that, high ALDOA expression was found to follow ER and PR positivity, while decreased ALDOA mRNA levels were associated with TNBC and basal‐like BC, which might indicate that steroids increase the levels of ALDOA in breast epithelial cells. Tubule formation, nuclear characteristics of pleiomorphism, and the mitotic index are all assessed by the SBR grade, a histological grade.20 NPI grade is a clinicopathological grading system based on tumor size, histopathological grade, and lymph node stage.21 Our study showed that ALDOA expression was higher with BC patients’ advanced SBR grade and NPI. Consistent with previous findings,22 ALDOA may predict a poorer prognosis in BC. Although a strong correlation between age and ALDOA expression was demonstrated in both databases, no such correlation was observed in the patient samples collected from individuals who underwent surgery. This is probably due to selection bias and a low sample size, because the clinical information for all 96 patients who underwent surgery was obtained from the same center. The clinicopathological information of BC patients from multiple centers need to be obtained in future subsequent studies.

    The KM plotter was used in this study to assess the relationship between BC patients’ survival and ALDOA expression. The survival curves showed higher ALDOA mRNA levels were generally linked to worse OS, worse RFS, and worse DMFS. This is in line with earlier findings that suggested high ALDOA levels are linked to poor patient survival in a variety of solid tumors, including BC.23 However, ALDOA expression was correlated to better DMFS of BC patients with LNM, which disagreed with the overall tendency and previous study.22

    Tu et al found that ALDOA can control tumor progression through the ALDOA-adenosine-50-monophosphate (AMP) activated protein kinase (AMPK) pathway, a nutrient sensor linked to aberrant activation of metabolic pathways, mitochondrial dynamics and functions, and epigenetic regulation. Depending on the specific cellular context, AMPK can be an oncogene or a tumor suppressor. Studies have shown the significance of ALDOA in cancers, but the underlying mechanisms are still unclear.22,24 In intrahepatic cholangiocarcinoma and radioresistance cervical cancer, ALDOA promotes tumor proliferation and migration by enhancing tumor cell glycolysis.9,25 According to Gu et al, ADOLA controlled the activity of the EGFR receptor and its downstream targets, ERK1/2 and AKT. Through the EGFR pathway, overexpression of ALDOA increased gastric cancer cells’ proliferation and cisplatin resistance.26 Research conducted by Lu et al has shown that ALDOA promoted the proliferation and metastasis of colorectal cancer through its interaction with and regulation of the protein COPS6, thereby activating the mitogen-activated protein kinase (MAPK) signaling pathway and initiating EMT.27 By suppressing miR-145 expression and activating the Oct4/DUSP4/TRAF4 pathway, ALDOA enhances the stemness of lung cancer.28

    There are some limitations in our study. Firstly, more research is necessary to understand the fundamental molecular process of ALDOA in BC cells. Secondly, more BC tumor tissues should be collected to further explore the expression and prognostic value of ALDOA in BC.

    These findings indicated that ALDOA expression was much higher in BC tissues and closely correlated with clinical characteristics. For BC patients, a higher ALDOA indicated a lower chance of survival. The current research suggests that ALDOA may be a significant prognostic factor and a potential target for BC treatment.

    Abbreviations

    ALODA, Aldolase A; BC, breast cancer; BLIA, basal-like immune-activated; BLIS, basal-like immune-suppressed; BRCA, breast cancer susceptibility gene; DMFS, distant metastasis-free survival; ER, estrogen receptor; FP, first progression; GES, gene expression signature; HER2, human epidermal growth factor receptor 2; IDC, invasive ductal carcinoma; IHC, immunohistochemistry staining; ILC, invasive lobular carcinoma; KM, Kaplan-Meier; LAR, luminal androgen receptor; LNM, lymph node metastasis; MLIA, mesenchymal-like immune-altered; NPI, Nottingham Prognostic Index; OS, overall survival; PAM50, intrinsic molecular subtypes from Parker’s SSP; PPS, post-progression survival; PR, progesterone receptor; RFS, relapse-free survival; SBR, Scarff-Bloom-Richardson; TNBC, triple negative breast cancer.

    Data Sharing Statement

    The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

    Ethics Statement

    The study was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University.

    Acknowledgments

    Yuning Dai, Yong Yang, Xiaohua Li, and Guojian Shi are co-first authors for this study. The authors greatly acknowledge the Central Research Laboratory, the First Affiliated Hospital of Soochow University, for their excellent support and assistance in this work, and thank MJEditor (www.mjeditor.com) for its linguistic assistance during the preparation of this manuscript.

    Author Contributions

    All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

    Funding

    This study was supported by the fund from the National Nature Science Foundation of China (82103362), the Project of Science and Technology Development Plan of Suzhou City of China (SKY2023151, SKY2023155 and SKJY2021073), the Reserve Talent Project of the First Affiliated Hospital of Soochow University, the Project of Jiangsu Maternal and Child Health Association (FYX202216), the Project of “Gusu Medical Star” Youth Talent of Suzhou City of China, and the Project of Beijing Science and Technology Medical Development Foundation (KC2021-JF-0167-09).

    Disclosure

    The authors declare no competing interests in this work.

    References

    1. Montazeri Aliabadi H. Molecular targets for breast cancer therapy. Biomolecules. 2024;14(10):1219. doi:10.3390/biom14101219

    2. Zhang D, Xu X, Ye Q. Metabolism and immunity in breast cancer. Front Med. 2021;15(2):178–207. doi:10.1007/s11684-020-0793-6

    3. Gohari N, Abbasi E, Akrami H. Comprehensive analysis of the prognostic value of glutathione S-transferases Mu family members in breast cancer. Cell Biol Int. 2024;48(9):1313–1325. doi:10.1002/cbin.12195

    4. Ma D, Chen X, Zhang PY, et al. Upregulation of the ALDOA/DNA-PK/p53 pathway by dietary restriction suppresses tumor growth. Oncogene. 2018;37(8):1041–1048. doi:10.1038/onc.2017.398

    5. Niu Y, Lin Z, Wan A, et al. Loss-of-function genetic screening identifies aldolase A as an essential driver for liver cancer cell growth under hypoxia. Hepatology. 2021;74(3):1461–1479. doi:10.1002/hep.31846

    6. Chen L, Wu Z, Guo J, et al. Initial clinical and experimental analyses of ALDOA in gastric cancer, as a novel prognostic biomarker and potential therapeutic target. Clin Exp Med. 2023;23(6):2443–2456. doi:10.1007/s10238-022-00952-8

    7. Song J, Li H, Liu Y, et al. Aldolase A accelerates cancer progression by modulating mRNA translation and protein biosynthesis via noncanonical mechanisms. Adv Sci. 2023;10(26):e2302425. doi:10.1002/advs.202302425

    8. Xu M, Xi S, Li H, et al. Prognosis significance and potential association between ALDOA and AKT expression in colorectal cancer. Sci Rep. 2024;14(1):6488. doi:10.1038/s41598-024-57209-5

    9. Zhou J, Lei N, Qin B, et al. Aldolase A promotes cervical cancer cell radioresistance by regulating the glycolysis and DNA damage after irradiation. Cancer Biol Ther. 2023;24(1):2287128. doi:10.1080/15384047.2023.2287128

    10. Huang Z, Hua Y, Tian Y, et al. High expression of fructose-bisphosphate aldolase A induces progression of renal cell carcinoma. Oncol Rep. 2018;39(6):2996–3006. doi:10.3892/or.2018.6378

    11. Wang Y, Tang J, Liu Y, et al. Targeting ALDOA to modulate tumorigenesis and energy metabolism in retinoblastoma. iScience. 2024;27(9):110725. doi:10.1016/j.isci.2024.110725

    12. Yu S, Wu R, Si Y, et al. Alternative splicing of ALDOA confers tamoxifen resistance in breast cancer. Oncogene. 2024;43(39):2901–2913. doi:10.1038/s41388-024-03134-w

    13. Jiang Z, Wang X, Li J, et al. Aldolase A as a prognostic factor and mediator of progression via inducing epithelial-mesenchymal transition in gastric cancer. J Cell Mol Med. 2018;22(9):4377–4386. doi:10.1111/jcmm.13732

    14. Tian W, Zhou J, Chen M, et al. Bioinformatics analysis of the role of aldolase A in tumor prognosis and immunity. Sci Rep. 2022;12(1):11632. doi:10.1038/s41598-022-15866-4

    15. Tang Y, Yang X, Feng K, et al. High expression of aldolase A is associated with tumor progression and poor prognosis in hepatocellular carcinoma. J Gastrointest Oncol. 2021;12(1):174–183. doi:10.21037/jgo-20-534

    16. Chang YC, Yang YC, Tien CP, et al. Roles of aldolase family genes in human cancers and diseases. Trends Endocrinol Metab. 2018;29(8):549–559. doi:10.1016/j.tem.2018.05.003

    17. Sun L, Yang X, Huang X, et al. 2-hydroxylation of fatty acids represses colorectal tumorigenesis and metastasis via the YAP transcriptional axis. Cancer Res. 2021;81(2):289–302. doi:10.1158/0008-5472.CAN-20-1517

    18. Lu T, Sun L, Fan Q, et al. Expression and clinical significance of ECHS1 in gastric cancer. J Cancer. 2024;15(2):418–427. doi:10.7150/jca.88604

    19. Ye F, Dewanjee S, Li Y, et al. Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer. Mol Cancer. 2023;22(1):105. doi:10.1186/s12943-023-01805-y

    20. Zhang M, Chen H, Wang M, et al. Bioinformatics analysis of prognostic significance of COL10A1 in breast cancer. Biosci Rep. 2020;40(2):1.

    21. Wang Q, Zhao S, Gan L, et al. Bioinformatics analysis of prognostic value of PITX1 gene in breast cancer. Biosci Rep. 2020;40(9). doi:10.1042/BSR20202537

    22. Tu Z, Hou S, Zheng Y, et al. In vivo library screening identifies the metabolic enzyme aldolase A as a promoter of metastatic lung colonization. iScience. 2021;24(5):102425. doi:10.1016/j.isci.2021.102425

    23. Cho EJ, Devkota AK, Stancu G, et al. A robust and cost-effective luminescent-based high-throughput assay for Fructose-1,6-Bisphosphate aldolase A. SLAS Discov. 2020;25(9):1038–1046. doi:10.1177/2472555220926146

    24. Hsu CC, Peng D, Cai Z, et al. AMPK signaling and its targeting in cancer progression and treatment. Semi Cancer Biol. 2022;85:52–68. doi:10.1016/j.semcancer.2021.04.006

    25. Li X, Yu C, Luo Y, et al. Aldolase A enhances intrahepatic cholangiocarcinoma proliferation and invasion through promoting glycolysis. Int J Bio Sci. 2021;17(7):1782–1794. doi:10.7150/ijbs.59068

    26. Gu M, Jiang B, Li H, et al. Aldolase A promotes cell proliferation and cisplatin resistance via the EGFR pathway in gastric cancer. Am J Transl Res. 2022;14(9):6586–6595.

    27. Lu Y, Zhang Y, Wang X, et al. Aldolase A promotes colorectal cancer progression through targeting COPS6 and regulating MAPK signaling pathway. Dis Markers. 2023;2023:1702125. doi:10.1155/2023/1702125

    28. Chang YC, Yang YF, Chiou J, et al. Nonenzymatic function of aldolase A downregulates miR-145 to promote the Oct4/DUSP4/TRAF4 axis and the acquisition of lung cancer stemness. Cell Death Dis. 2020;11(3):195. doi:10.1038/s41419-020-2387-2

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